Inflammatory skin diseases and the risk of chronic kidney disease: population-based case-control and cohort analyses.

BACKGROUND: Emerging evidence suggests an association between common inflammatory skin diseases and chronic kidney disease (CKD). OBJECTIVES: To explore the association between CKD stages 3-5 (CKD3-5) and atopic eczema, psoriasis, rosacea and hidradenitis suppurativa. METHODS: We undertook two complementary analyses; a prevalent case-control study and a cohort study using routinely collected primary care data [UK Clinical Practice Research Datalink (CPRD)]. We matched individuals with CKD3-5 in CPRD in March 2018 with up to five individuals without CKD for general practitioner practice, age and sex. We compared the prevalence of CKD3-5 among individuals with and without each inflammatory skin disease. We included individuals in CPRD with diabetes mellitus (2004-2018) in a cohort analysis to compare the incidence of CKD3-5 among people with and without atopic eczema and psoriasis. RESULTS: Our study included 56 602 cases with CKD3-5 and 268 305 controls. Cases were more likely than controls to have a history of atopic eczema [odds ratio (OR) 1·14, 99% confidence interval (CI) 1·11-1·17], psoriasis (OR 1·13, 99% CI 1·08-1·19) or hidradenitis suppurativa (OR 1·49, 99% CI 1·19-1·85), but were slightly less likely to have been diagnosed with rosacea (OR 0·92, 99% CI 0·87-0·97), after adjusting for age, sex, practice (matching factors), index of multiple deprivation, diabetes, smoking, harmful alcohol use and obesity. Results remained similar after adjusting for hypertension and cardiovascular disease. In the cohort with diabetes (N = 335 827), there was no evidence that CKD3-5 incidence was associated with atopic eczema or psoriasis. CONCLUSIONS: Atopic eczema, psoriasis and hidradenitis suppurativa are weakly associated with CKD3-5. Future research is needed to elucidate potential mechanisms and the clinical significance of our findings.

High prevalence of albuminuria amongst people who inject drugs: A cross-sectional study.

Albuminuria is a key biomarker for cardiovascular disease and chronic kidney disease. Our study aimed to describe the prevalence of albuminuria amongst people who inject drugs in London and to test any potential associations with demographic characteristics, past diagnoses, and drug preparation and administration practices. We carried out a cross-sectional survey amongst people who use drugs in London. The main outcome measure was any albuminuria including both microalbuminuria and macroalbuminuria. Three-hundred and sixteen samples were tested by local laboratory services. Our study initially employed point-of-care testing methods but this resulted in a high number of false positives. Our findings suggest the prevalence of albuminuria amongst PWID is twice that of the general population at 19% (95%CI 15.3-24.0%). Risk factors associated with albuminuria were HIV (aOR 4.11 [95% CI 1.37-12.38]); followed by overuse of acidifier for dissolving brown heroin prior to injection (aOR 2.10 [95% CI 1.04-4.22]). Albuminuria is high amongst people who inject drugs compared to the general population suggesting the presence of increased cardiovascular and renal pathologies. This is the first study to demonstrate an association with acidifier overuse. Dehydration may be common amongst this population and may affect the diagnostic accuracy of point-of-care testing for albuminuria.

Ecological Study of HIV Infection and Hypertension in Sub-Saharan Africa: Is There a Double Burden of Disease?

METHODS: Data on prevalence of hypertension were derived from a systematic search of literature published between 1975 and 2014 with corresponding national estimates on HIV prevalence and antiretroviral therapy (ART) coverage from the Demographic and Health Surveys and the joint United Nations Programme on HIV/AIDS databases. National estimates on gross national income (GNI) and under-five mortality were obtained from the World Bank database. Linear regression analyses using robust standard errors (allowing for clustering at country level) were carried out for associations of age-standardised hypertension prevalence ratios (standardized to rural Uganda's hypertension prevalence data) with HIV prevalence, adjusted for national indicators, year of study and sex of the study population. RESULTS: In total, 140 estimates of prevalence of hypertension representing 25 nations were sex-and area-matched with corresponding HIV prevalence. A two-fold increase in HIV prevalence was associated with a 9.29% increase in age, sex and study year-adjusted prevalence ratio for hypertension (95% CI 2.0 to 16.5, p = 0.01), which increased to 16.3% (95% CI 9.3 to 21.1) after adjusting for under-five mortality, GNI per capita and ART coverage. CONCLUSIONS: Countries with a pronounced burden of HIV may also have an increased burden of non-communicable diseases such as hypertension with potential economic and health systems implications.

Acute kidney injury in stable COPD and at exacerbation.

BACKGROUND: While acute kidney injury (AKI) alone is associated with increased mortality, the incidence of hospital admission with AKI among stable and exacerbating COPD patients and the effect of concurrent AKI at COPD exacerbation on mortality is not known. METHODS: A total of 189,561 individuals with COPD were identified from the Clinical Practice Research Datalink. Using Poisson and logistic regressions, we explored which factors predicted admission for AKI (identified in Hospital Episode Statistics) in this COPD cohort and concomitant AKI at a hospitalization for COPD exacerbation. Using survival analysis, we investigated the effect of concurrent AKI at exacerbation on mortality (n=36,107) and identified confounding factors. RESULTS: The incidence of AKI in the total COPD cohort was 128/100,000 person-years. The prevalence of concomitant AKI at exacerbation was 1.9%, and the mortality rate in patients with AKI at exacerbation was 521/1,000 person-years. Male sex, older age, and lower glomerular filtration rate predicted higher risk of AKI or death. There was a 1.80 fold (95% confidence interval: 1.61, 2.03) increase in adjusted mortality within the first 6 months post COPD exacerbation in patients suffering from AKI and COPD exacerbation compared to those who were AKI free. CONCLUSION: In comparison to previous studies on general populations and hospitalizations, the incidence and prevalence of AKI is relatively high in COPD patients. Coexisting AKI at exacerbation is prognostic of poor outcome.

Urbanization and non-communicable disease in Southeast Asia: a review of current evidence.

OBJECTIVE: Non-communicable diseases (NCDs) have been highlighted as a major public health issue in the Southeast (SE) Asian region. One of the major socio-environmental factors that are considered to be associated with such a rise in NCDs is urbanization. Urbanization is associated with behavioural changes such as eating an unhealthy diet, and a decrease in physical activities, which may result in associated obesity. The SE Asian region also has a substantive burden of infectious disease such as HIV and malaria, which may modify associations between urbanization and development of NCDs. STUDY DESIGN: A systematic review was conducted until April 2013. METHODS: Using four databases: EMBASE, PubMed, GlobalHealth and DigitalJournal, the systematic review pools existing evidence on urban-rural gradients in NCD prevalence/incidence. RESULTS: The study found that in SE Asia, urban exposure was positively associated with coronary heart disease, diabetes and respiratory diseases in children. Urban exposure was negatively associated with rheumatic heart diseases. The stages of economic development may also modify the association between urbanization and NCDs such as diabetes. CONCLUSION: There was pronounced heterogeneity between associations. It is recommended that future studies examine the major constituents of NCDs separately and also focus on the interplay between lifestyle and infectious risk factors for NCDs. Prospective studies are needed to understand the diverse causal pathways between urbanization and NCDs in SE Asia.

New estimates of the burden of acute community-acquired infections among older people with diabetes mellitus: a retrospective cohort study using linked electronic health records.

AIM: To describe the incidence of acute community-acquired infections (lower respiratory tract infections, urinary tract infections and sepsis) among the UK population aged ≥65 years with diabetes mellitus, and all-cause 28-day hospital admission rates and mortality. METHODS: We used electronic primary care records from the Clinical Practice Research Datalink, linked to death certificates and Hospital Episode Statistics admission data, to conduct a retrospective cohort study from 1997 to 2011. RESULTS: Among the 218 805 older people with diabetes there was a high burden of community-acquired infection, lower respiratory tract infections having the highest incidence (crude rate: 152.7/1000 person-years) followed by urinary tract infections (crude rates 51.4 and 147.9/1000 person-years for men and women, respectively). The incidence of all infections increased over time, which appeared to be driven by the population's changing age structure. Most patients diagnosed with pneumonia and sepsis were hospitalized on the same day (77.8 and 75.1%, respectively). For lower respiratory tract infections and urinary tract infections, a large proportion of 28-day hospitalizations were after the day of diagnosis (39.1 and 44.3%, respectively), and a notable proportion of patients (7.1 and 5.1%, respectively) were admitted for a cardiovascular condition. In the 4 weeks after onset, all-cause mortality was 32.1% for pneumonia (3115/9697), 31.7% for sepsis (780/2461), 4.1% for lower respiratory tract infections (5685/139 301) and 1.6% for urinary tract infections (1472/91 574). CONCLUSIONS: The present large cohort study provides up-to-date detailed infection incidence estimates among older people with diabetes in the community, with variation by age, sex and region and over time. This should be of use for patient communication of risk and future healthcare planning.

Constituent country inequalities in myocardial infarction incidence and case fatality in men and women in the United Kingdom, 1996-2005.

BACKGROUND: Understanding myocardial infarction (MI) incidence and case fatality trends across the four UK constituent countries is of importance following devolution of the government of health-care services. METHODS: Retrospective cohort study using a primary care database (5.19 million patients) examining trends in incidence of first MI and 30-day case fatality. RESULTS: From 1996 to 2005, the incidence of MI decreased in all countries, but reductions were greater in England (men, -3.1%; women, -2.8%) and Wales (men, -3.3%; women, -4.6%) than in Scotland (men, -1.9%; women, -0.6%) and Northern Ireland (men no change, women, -0.8%) (average annual percentage change). Greater reductions in England and Wales than Scotland and Northern Ireland meant a widening of north-south difference in MI incidence over the study period. Downward trends in 30-day case fatality were found in each country but less regional variation was evident (England men, -12.0%, women, -11.0%; Wales men, -18.4%, women, -12.6%; Scotland men, -9.5%, women, -9.0%; Northern Ireland men, -8.6%, women, -13.0%). CONCLUSION: From 1996 to 2005, downward trends in the incidence of first MI and 30-day case fatality were evident in each constituent country. Greater improvements in case fatality, compared with incidence, were found within each country.

Validation and utility of a computerized South Asian names and group recognition algorithm in ascertaining South Asian ethnicity in the national renal registry.

BACKGROUND: The UK Renal Registry (UKRR) reports on equity and quality of renal replacement therapy (RRT). Ethnic origin is a key variable, but it is only recorded for 76% patients overall in the UKRR and there is wide variation in the degree of its completeness between renal centres. Most South Asians have distinctive names. AIM: To test the relative performance of a computerized name recognition algorithm (SANGRA) in identifying South Asian names using the UKRR database. DESIGN: Cross-sectional study of patients (n = 27 832) starting RRT in 50 renal centres in England and Wales from 1997 to 2005. METHODS: Kappa statistics were used to assess the degree of agreement of SANGRA coding with existing ethnicity information in UKRR centres. RESULTS: In 12 centres outside London (number of patients = 7555) with 11% (n = 747) self-ascribed South Asian ethnicity, the level of agreement between SANGRA and self-ascribed ethnicity was high (kappa=0.91, 95% CI 0.90-0.93). In two London centres (n = 779) with 21% (n = 165) self-ascribed South Asian ethnicity, SANGRA's agreement with self-ascribed ethnicity was lower (kappa=0.60, 95% CI 0.54-0.67), primarily due to difficulties in distinguishing between South Asian ethnicity and other non-White ethnic minorities. Use of SANGRA increased numbers defined as South Asian from 1650 to 2076 with no overall change in percentage of South Asians. Kappa values showed no obvious association with degree of missing data returns to the UKRR. CONCLUSION: SANGRA's use, taking into account its lower validity in London, allows increased power and generalizability for both ethnic specific analyses and for analyses where adjustment for ethnic origin is important.

The heritability and genetics of complement C3 expression in UK SLE families.

As the central component of the complement system, C3 has sensory and effector functions bridging innate and adaptive immunity. It is plausible that common genetic variation at C3 determines either serum C3 level or susceptibility to systemic lupus erythematosus (SLE), but only a single, Japanese, study has currently showed genetic association. In a cohort of 1371 individuals from 393 UK white European SLE families, we quantified serum C3 and genotyped C3 tagSNPs. Using a Bayesian variance components model, we estimated 39.6% serum C3 heritability. Genotype/serum C3 association was determined by mixed linear models. Single nucleotide polymorphism (SNP) rs344555, located in a haplotype block incorporating the 3' end of C3, was associated with serum C3 (P=0.007), with weaker associations observed for other SNPs in this block. In an extended cohort of 585 SLE families the association between C3 variants and SLE was assessed by transmission disequilibrium test. SNP rs3745568 was associated with SLE (P=0.0046), but not with serum C3. Our disease associated SNP differs from that highlighted in the Japanese study; however, we replicate their finding that genetic variants at the 3' end of C3 are associated with serum C3. Larger studies and further fine mapping will be required to definitively identify functional variants.

Patients with diabetic nephropathy on renal replacement therapy in England and Wales.

BACKGROUND: The incidence of patients with diabetic nephropathy (DN) who start renal replacement therapy (RRT) is increasing. AIM: To describe the characteristics and survival of patients with DN starting RRT in the UK. DESIGN: Retrospective cohort study. METHODS: We analysed data for incident patients on RRT in centres participating in the Renal Association UK Renal Registry (UKRR), 1997 -2004, comparing DN vs. non-DN patients with regard to survival, social deprivation, ethnicity, gender, and age, using Cox regression models. RESULTS: DN was the most common renal disease (19%) in the 20 532 patients starting RRT. The majority of patients with DN (77%) were Caucasian. Within the Caucasian population, DN patients were more likely to be from a socially deprived area (p < 0.0001). About 20% were referred <3 months before starting RRT. The difference in crude survival was greatest in younger patients (5-year survival was 56% (DN) vs. 85% (non-DN) in patients aged 18-54 years, and 17% (DN) vs. 28% (non-DN) in patients aged >or=65 years). Despite adjusting for gender, age, treatment modality, social deprivation, referral and co-morbidities, the long-term prognosis for DN patients aged 18-54 years was worse (adjusted hazard ratio 2.13, 95%CI 1.23-3.67) than for older age groups. DISCUSSION: Patients with DN starting RRT are more likely to come from socially deprived areas. Relative risk of death is greatest in working-age DN patients and is not fully explained by recorded co-morbidity. This emphasizes the need for focused diabetes care in poorer areas, and assessment of quality of care of diabetic patients on RRT.

Social deprivation and survival on renal replacement therapy in England and Wales.

This study examines the association between social deprivation and patient characteristics and outcomes in a nationally representative cohort of incident renal replacement therapy (RRT) patients. All Caucasian patients reported to the UK Renal Registry between 1997 and 2004 by centers in England and Wales with high data completeness were included. Social deprivation was assessed using the Townsend index. Socially deprived patients were more likely to be referred late. They were less likely to receive peritoneal dialysis (25.1 vs 34.8% on day 1, P trend <0.0001) or a renal transplant (5.3 vs 12.4% at 1 year, P trend <0.0001), and were less likely to attain UK Renal Association standards for hemoglobin and phosphate at 1 year. Crude survival decreased significantly with increasing deprivation for patients under the age of 65 years, but not for those aged 65 years and above (likelihood ratio for age-social deprivation interaction P<0.0001). Social deprivation was significantly associated with poorer survival after adjustment for age, gender, and cause of renal failure. After adjusting for baseline co-morbidity, social deprivation was no longer associated with poorer survival. Baseline differences in co-morbidity seem to explain poorer crude survival in incident Caucasian RRT patients from socially deprived areas in England and Wales. Differences also exist in some processes of care and intermediate outcomes, which may be amenable to intervention.

No association between E- and L-selectin genes and SLE: soluble L-selectin levels do correlate with genotype and a subset in SLE.

Altered function of selectin glycoprotein adhesion molecules may modulate severity and organ-specific manifestations of autoimmune and inflammatory disease via changes in leukocyte trafficking. Serum concentrations of selectin molecules have been suggested as useful biomarkers in systemic lupus erythematosus (SLE). We identified increased levels of soluble L-selectin (sL-selectin), but not soluble E-selectin (sE-selectin) in 278 European-Caucasian lupus patients compared to 230 healthy siblings (P=0.002). sL-selectin levels were markedly elevated in patients with IgG antiphospholipid autoantibodies (P=0.002), suggesting that perhaps sL-selectin defines a subgroup of lupus with vasculopathy. sL-selectin level was also influenced by two L-selectin polymorphisms: 665C>T, F206L in the epidermal growth factor-like domain (P=0.015) and rs12938 in the 3'-untranslated region (P=0.06). Having shown increased sL-selectin levels in lupus patients, we used genetics to investigate whether this was a secondary phenomena or the result of an underlying genetic mechanism. The inheritance of nine single-nucleotide polymorphisms (SNP) spanning the selectin locus was tested in 523 UK simplex SLE families. No association with SLE, or related phenotypes, was evident with any single SNP, or haplotype in family-based tests of association. Selectin polymorphisms are, therefore, unlikely to be independent factors in SLE susceptibility.

Apoptosis and expression of inducible nitric oxide synthase are mutually exclusive in renal mesangial cells.

Nitric oxide (NO) is a multipurpose messenger molecule, important for blood vessel relaxation, neuronal communication, and antimicrobial activities. The generation of NO from L-arginine is catalyzed by NO synthase (NOS). An inducible form of NOS, iNOS, was first characterized in macrophages and then in many other tissues and cells, including renal mesangial cells. Mesangial cells play a crucial role in the regulation of the glomerular filtration rate as well as in the pathophysiology of certain forms of glomerulonephritis in which mesangial cells and macrophages produce NO in high amounts. Because reports have associated NO production with apoptotic cell death in macrophages and we recently demonstrated NO-mediated apoptosis in mesangial cells, we searched for the relationship between in situ iNOS induction and apoptosis by iNOS immunocytochemistry and terminal desoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. RAW 264.7 macrophages exhibited homogeneous iNOS expression and apoptotic nuclei in the iNOS-containing cells upon stimulation with interferon-gamma and lipopolysaccharide. In contrast, stimulated rat mesangial cells stained heterogeneously for iNOS, depending on cell passage and iNOS-stimulating pathway. Mesangial cells expressing iNOS did not display signs of apoptosis and, vice versa, cells showing characteristic features of apoptosis did not stain for iNOS. Thus, our study suggests that mesangial cells react to stimulation by interleukin-1 and/or cAMP-elevating compounds with mutually exclusive responses, either by expression of iNOS or by undergoing programmed cell death.

Apoptosis is triggered by the cyclic AMP signalling pathway in renal mesangial cells.

Glomerular mesangial cells are regarded as specialized smooth muscle cells located within the renal glomeruli and fulfilling important functions in glomerular physiology and pathophysiology. Here, we report that activation of the cyclic AMP signalling pathway by dibutyryl cyclic AMP, forskolin, or the beta 2-adrenergic receptor agonist salbutamol results in induction of apoptosis in mesangial cells. Activation of the apoptotic programme results in DNA fragmentation which is visible for most forms of apoptosis and is paralleled by enrichment of cytosolic DNA/histone complexes, an increasing number of cellular 3'-OH-fragmented DNA ends and typical nuclear chromatin condensation. Induction of apoptosis was found to be dependent on translation and independent of nitric oxide synthase activity.

Therapeutic strategies for the inhibition of inducible nitric oxide synthase--potential for a novel class of anti-inflammatory agents.

In recent years, NO, a gas previously considered a potentially toxic chemical, has become established as a diffusible universal messenger mediating cell-cell communication throughout the body. In mammals, NO is a recognized mediator of blood vessel relaxation that helps to maintain blood pressure. In the central nervous system NO acts as a non-conventional neurotransmitter and participates in the establishment of long-term plasticity required for memory formation. In addition, NO is responsible for some parts of the host response to sepsis and inflammation and contributes to certain disease states. A number of strategies have emerged with regard to a pharmacological control of pathological NO overproductions. This review will discuss these novel therapeutic approaches that may provide new means for clinical medicine.

Interleukin 1 beta-induced expression of nitric oxide synthase in rat renal mesangial cells is suppressed by cyclosporin A.

The expression of inducible nitric oxide synthase (iNOS) is triggered in rat renal mesangial cells by exposure to the inflammatory cytokine interleukin 1 beta (IL-1 beta). Here we report that cyclosporin A (CsA) a potent immunosuppressive drug, inhibits IL-1 beta dependent iNOS expression in renal mesangial cells. Addition of CsA dose dependently suppresses IL-1 beta-induced nitrite formation (IC50 = 0.9 microM). Western- and Northern blot analyses of mesangial cell extracts reveal that the inhibition of IL-1 beta-induced nitrite formation by CsA is due to decreased iNOS protein and iNOS mRNA steady state levels. Using nuclear run on experiments we show that the transcription rate of the IL-1 beta-induced iNOS gene is reduced. Furthermore, by electrophoretic mobility shift analysis we demonstrate reduced DNA-binding of the nuclear factor NF kappa B, an essential component of the IL-1 beta-dependent upregulation of iNOS gene transcription. The data presented in this report suggest that the cellular machinery involved in the IL-1 beta dependent transcriptional upregulation of the iNOS gene in mesangial cells is a target for the action of CsA.

Role of cyclic AMP in the control of cell-specific gene expression.

Genes have to be expressed in specific cell types at appropriate times of development dependent on external signals. cAMP signaling occurs in all cells, thus raising the question of how this signal transduction pattern is integrated into mechanisms determining cell-specific gene expression. We have analyzed expression of the tyrosine aminotransferase gene as a model to study the basis of this cell type specificity of hormone induction. We found that cell-type-specific expression is generated by combined action of cAMP signal-dependent and liver cell-specific transcription factors. The interdependence of the cAMP response element and an element determining liver cell specificity enables a gene to respond to an ubiquitous signal in a cell-specific manner.

The distal enhancer implicated in the developmental regulation of the tyrosine aminotransferase gene is bound by liver-specific and ubiquitous factors.

Tyrosine aminotransferase gene expression is confined to parenchymal cells of the liver, is inducible by glucocorticoids and glucagon, and is repressed by insulin. Three enhancers control this tissue-specific and hormone-dependent activity, one of which, located at -11 kb, is implicated in establishing an active expression domain. We have studied in detail this important regulatory element and have identified a 221-bp fragment containing critical enhancer sequences which stimulated the heterologous thymidine kinase promoter more than 100-fold in hepatoma cells. Within this region, we have characterized two essential liver-specific enhancer domains, one of which was bound by proteins of the hepatocyte nuclear factor 3 (HNF3) family. Analyses with the dedifferentiated hepatoma cell line HTC suggested that HNF3 alpha and/or -gamma, but not HNF3 beta, are involved in activating the tyrosine aminotransferase gene via the -11-kb enhancer. Genomic footprinting and in vitro protein-DNA binding studies documented cell-type-specific binding of ubiquitous factors to the second essential enhancer domain, which by itself stimulated the thymidine kinase promoter preferentially in hepatoma cells. These results will allow further characterization of the role of these enhancer sequences in developmental activation of the tyrosine aminotransferase gene.

Extinction of gene expression in somatic cell hybrids--a reflection of important regulatory mechanisms?

Extinction in somatic cell hybrids is a multifactorial process that leads to loss of cell-type-specific gene expression. The underlying mechanisms are thought to mirror, at least in part, the repertoire of regulatory mechanisms controlling mammalian cell differentiation.

Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elements.

Tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5) gene activity is stimulated by glucocorticoids and glucagon and is repressed by insulin. Expression and responsiveness to the different signal transduction pathways are restricted to the liver, in which the gene is activated shortly after birth. Here we provide a model for the basis of this tissue specificity of the hormonal control. In the two enhancers mediating hormone induction of TAT gene activity we find the hormone response elements in combination with binding sites for constitutive liver-enriched transcription factors: proteins of the hepatocyte nuclear factor 3 family bind in the vicinity of the glucocorticoid response element located 2.5 kb upstream of the transcription start site, while hepatocyte nuclear factor 4 interacts with an essential element in the cAMP-responsive enhancer at -3.6 kb. By juxtaposing the liver-specific element and the target sequence of the signal transduction pathway the regulatory properties of either enhancer can be reconstituted. Thus, the interdependence of the respective enhancer motifs restricts the hormonal activation of the TAT gene to the liver. The coincidence of the onset of TAT gene expression around birth with the perinatal changes in the concentrations of glucocorticoids, glucagon, and insulin suggests cooperation of signal transduction pathways and cell type-specific transcription factors in the developmental activation of the TAT gene.