Protein kinase C activation and its role in kidney disease

Protein kinase C (PKC) comprises a superfamily of isoenzymes, many of which are activated by cofactors such as diacylglycerol and phosphatidylserine. In order to be capable of activation, PKC must first undergo a series of phosphorylations. In turn, activated PKC phosphorylates a wide variety of intracellular target proteins and has multiple functions in signal transduced cellular regulation. A role for PKC activation had been noted in several renal diseases, but two that have had most investigation are diabetic nephropathy and kidney cancer. In diabetic nephropathy, an elevation in diacylglycerol and/or other cofactor stimulants leads to an increase in activity of certain PKC isoforms, changes that are linked to the development of dysfunctional vasculature. The ability of isoform-specific PKC inhibitors to antagonize diabetes-induced vascular disease is a new avenue for treatment of this disorder. In the development and progressive invasiveness of kidney cancer, increased activity of several specific isoforms of PKC has been noted. It is thought that this may promote the kidney cancer's inherent resistance to apoptosis, in natural regression or after treatments, or it may promote the invasiveness of renal cancers via cellular differentiation pathways. In general, however, a more complete understanding of the functions of individual PKC isoforms in the kidney, and development or recognition of specific inhibitors or promoters of their activation, will be necessary to apply this knowledge for treatment of cellular dysregulation in renal disease.

Polycystic kidney disease in Bull Terriers: an autosomal dominant inherited disorder

The prevalence, mode of inheritance and urinalysis findings in Bull Terriers with polycystic kidney disease were assessed by screening 150 clinically normal dogs. The disorder was diagnosed in 39 dogs on the basis of renal ultrasound results and family history of the disease. In equivocal cases confirmation required gross and histopathological renal examination. Necropsy was performed on nine affected dogs and the kidneys from another five affected animals were also examined. Renal cysts were usually bilateral, occurred in cortex and medulla and varied from less than 1 mm to over 2.5 cm in diameter. Cysts were lined by epithelial cells of nephron origin. Abnormal urine sediment and proteinuria were common in affected dogs. The disease appears to be inherited in a highly penetrant autosomal dominant manner.

Decreased Cell Wall Galactosaminogalactan in Aspergillus nidulans Mediates Dysregulated Inflammation in the Chronic Granulomatous Disease Host

Author Disclosure Statement No competing financial interests exist.

Long term effects of gestational hypertension and pre-eclampsia on kidney function : Record linkage study

This research was funded by the Chief Scientists Office, Scotland (CZH/4/659).

Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)

Peer reviewed

Novel Genetic Determinants of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a devastating diabetes complication, with known heritability not fully revealed by previous genetics studies. We performed the largest genome-wide association study of type 1 DKD to date, in a 13-cohort consortium of 15,590 individuals of European ancestry genotyped on the Illumina HumanCoreExome Beadchip, which allows exploration of coding variation in addition to genomic markers.

As prior work has shown that different characterizations of the DKD phenotype highlight distinct genetic associations, we investigated a spectrum of DKD definitions based on proteinuria and renal function criteria. Controls were DKD-free after a minimum of 15 years diabetes duration; cases had diabetes for at least 10 years prior to DKD diagnosis. We also performed a quantitative trait analysis of estimated glomerular filtration rate in all participants.

Our top finding was a missense mutation in COL4A3, rs55703767 (Asp326Tyr); the minor allele is common in Europeans (20%) and East Asians (13%) but not Africans (2%). This SNP had a genome-wide significant association with traditionally defined DKD (macroalbuminuria or end-stage renal disease [ESRD], (OR= 0.79, P=1.9×10-9), and a suggestive association with macroalbuminuria (OR= 0.79, P=1.6×10-6) and ESRD (OR= 0.79, P=4.5×10-5) individually. Though its PolyPhen score is 0.3 (benign), this SNP has been implicated as a splice site disruptor.

The COL4A3 gene encodes the alpha 3 subunit of Type IV collagen, the major structural component of basement membranes. Pathogenic mutations in COL4A3 have been identified in thin basement membrane nephropathy, familial focal segmental glomerulosclerosis, and Alport syndrome. A proxy (r2=0.6) for rs55703767 had no significant associations in the CKDGen consortium, suggesting its pathogenicity occurs solely in the setting of hyperglycemia.

By significantly increasing sample size we have discovered a novel locus underlying DKD risk, paving the way for better understanding of pathology, prevention, and treatment.

Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)

Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.

Behavior change theory, content and delivery of interventions to enhance adherence in chronic respiratory disease: A systematic review

Background: We sought to describe the theory used to design treatment adherence interventions, the content delivered, and the mode of delivery of these interventions in chronic respiratory disease. Methods: We included randomized controlled trials of adherence interventions (compared to another intervention or control) in adults with chronic respiratory disease (8 databases searched; inception until March 2015). Two reviewers screened and extracted data: post-intervention adherence (measured objectively); behavior change theory, content (grouped into psychological, education and self-management/supportive, telemonitoring, shared decision-making); and delivery. “Effective” studies were those with p < 0.05 for adherence rate between groups. We conducted a narrative synthesis and assessed risk of bias. Results: 12,488 articles screened; 46 included studies (n = 42,91% in OSA or asthma) testing 58 interventions (n = 27, 47% were effective). Nineteen (33%) interventions (15 studies) used 12 different behavior change theories. Use of theory (n = 11,41%) was more common amongst effective interventions. Interventions were mainly educational, self-management or supportive interventions (n = 27,47%). They were commonly delivered by a doctor (n = 20,23%), in face-to-face (n = 48,70%), one-to-one (n = 45,78%) outpatient settings (n = 46,79%) across 2–5 sessions (n = 26,45%) for 1–3 months (n = 26,45%). Doctors delivered a lower proportion (n = 7,18% vs n = 13,28%) and pharmacists (n = 6,15% vs n = 1,2%) a higher proportion of effective than ineffective interventions. Risk of bias was high in >1 domain (n = 43, 93%) in most studies. Conclusions: Behavior change theory was more commonly used to design effective interventions. Few adherence interventions have been developed using theory, representing a gap between intervention design recommendations and research practice.

Impacto da Insuficiência Renal no Prognóstico dos Doentes Submetidos a Reparação de Aneurisma da Aorta Abdominal - Cirurgia Convencional vs. Tratamento Endovascular do Aneurisma da Aorta

Introdução: A correção cirúrgica do aneurisma da aorta abdominal (AAA), por Endovascular Aneurysm Repair (EVAR) ou cirurgia convencional (CC), pode agravar a função renal a curto prazo. Esta complicação, mais frequente nos doentes com insuficiência renal crónica (IRC), associa-se a pior prognóstico a longo prazo. O objetivo deste trabalho foi quantificar o agravamento da função renal após reparação do AAA em doentes com IRC prévia e demonstrar o consequente aumento da morbimortalidade. Métodos: Estudo retrospetivo em doentes com IRC estádios Chronic Kidney Disease 3-4 (TFGe 15-59ml/min), submetidos a correção eletiva de AAA entre fevereiro/2011 e fevereiro/2015 numa instituição terciária. Variáveis estudadas: idade, sexo, tipo de intervenção (convencional/EVAR) e estádio CKD. Endpoints: variação da creatinina e taxa de filtração glomerular com a cirurgia, complicações renais pós-operatórias, necessidade de reintervenção cirúrgica e mortalidade. A análise estatística foi realizada em SPSS. Resultados: Foram incluídos 71doentes. Quinze doentes (21%) foram operados por CC e 56 (78%) por EVAR. À data da intervenção, os doentes encontravam-se nos seguintes estádios da DRC: CKD 3 --- 65 (91%) e CKD 4 --- 6 (9%). A variac¸ão da TFG com a cirurgia foi −1,08±18,01mg/dl. Verificou-se IRC agudizada pós-operatória em 22 (31%) doentes e necessidade de diálise em 5 (7%). A mortalidade global foi 8,5%. Os doentes operados por EVAR tinham DRC mais avançada pré-operatoriamente, mas apresentaram menor agravamento da função renal. Variação TFG: EVAR 1,14±16,26ml/min vs. CC 9,40±22,11ml/min (p=0,022); variação creatinina: EVAR 0,17±1,03mg/dl vs. CC 0,81±1,47mg/dl (p=0,02). A agudização da IRC pós-operatória foi superior no grupo CC (53,3 vs. 28,6%; p=0,072), assim como a necessidade de diálise (20 vs. 3,6%, p=0,06). Os 6 doentes que faleceram (EVAR: 3; CC: 3) apresentaram maior agravamento da função renal (variação da creatinina: 1,41±1,63mg/dl vs. 0,20±1,07mg/dl, p=0,001; variação da TFG: −19,0±16,55ml/min; 0,57±17,34ml/min, p=0,007) e necessidade de diálise (50 vs. 3,1%, p=0,003). Conclusão: Os resultados demonstraram uma tendência para uma menor probabilidade de IRA, menor necessidade de diálise pós-operatória e menor mortalidade nos doentes tratados por EVAR. Contudo, o impacto da administração de contraste a médio/longo prazo, decorrente dos programas de vigilância pós-EVAR, deve ser considerado. Julgamos ser possível considerar que a realização de EVAR para o tratamento de doentes com AAA e IRC é um procedimento pelo menos tão seguro como a CC.

Brucella Non-Neutrocytic Bacterascites in a Patient with Chronic Liver Disease

Objectives: To report a case of Brucella peritonitis. Patient and methods: We describe the case of a patient and present a brief review of the few published reports. Results: The patient had alcoholic cirrhosis of the liver and was diagnosed with Brucella non-neutrocytic bacterascites. Conclusion: Brucellosis is a common zoonosis with worldwide distribution. It is a systemic disease with the potential to predominantly affect one organ or a specific system (focal brucellosis). However, peritoneal focalization of this disease is a very rare presentation.

Deficiencies in education and experience in the management of acute kidney injury among Malawian healthcare workers

Background Acute kidney injury (AKI) is a common but under-recognised disease process, which carries a high risk of mortality or chronic complications, such as chronic kidney disease and other organ dysfunction. Management of AKI, however, is suboptimal, both in developed settings and in Malawi. This is partly because of deficiencies in AKI education and training. Aim To establish current levels of AKI education in a range of healthcare workers in Malawi. Methods An AKI symposium was held in Blantyre in March 2015. Delegates were asked to complete a survey at the start of the symposium to assess their clinical experience and education in the management of AKI. Results From 100 delegates, 89 nurses, clinical officers, and physicians, originating from 11 different districts, responded to the survey. Twenty-two percent of healthcare workers (including 28% of district workers of the various cadres and 31% of nurses) had never received teaching on any aspect of renal disease, and 50% (including 63% of district workers and 61% of nurses) had never received teaching specifically on AKI. Forty-four percent did not feel confident managing AKI, and 98% wanted more support managing patients with renal disease. Thirty-four percent (including 55% of district workers) were unaware that haemodialysis was available at Queen Elizabeth Central Hospital (QECH) for the treatment of AKI and 53% (74% of district workers) were unaware that peritoneal dialysis was available for the treatment of AKI in children. Only 33% had ever referred a patient with AKI to QECH. Conclusions There are deficiencies in education about, and clinical experience in, the management of AKI among Malawian healthcare workers, in addition to limited awareness of the renal service available at QECH. Urgent action is required to address these issues in order to prevent morbidity and mortality from AKI in Malawi.

Commercial enzyme-linked immunosorbent assay versus polymerase chain reaction for the diagnosis of chronic Chagas disease: a systematic review and meta-analysis

Chronic Chagas disease diagnosis relies on laboratory tests due to its clinical characteristics. The aim of this research was to review commercial enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) diagnostic test performance. Performance of commercial ELISA or PCR for the diagnosis of chronic Chagas disease were systematically searched in PubMed, Scopus, Embase, ISI Web, and LILACS through the bibliography from 1980-2014 and by contact with the manufacturers. The risk of bias was assessed with QUADAS-2. Heterogeneity was estimated with the I2 statistic. Accuracies provided by the manufacturers usually overestimate the accuracy provided by academia. The risk of bias is high in most tests and in most QUADAS dimensions. Heterogeneity is high in either sensitivity, specificity, or both. The evidence regarding commercial ELISA and ELISA-rec sensitivity and specificity indicates that there is overestimation. The current recommendation to use two simultaneous serological tests can be supported by the risk of bias analysis and the amount of heterogeneity but not by the observed accuracies. The usefulness of PCR tests are debatable and health care providers should not order them on a routine basis. PCR may be used in selected cases due to its potential to detect seronegative subjects.

Serological based monitoring of a cohort of patients with chronic Chagas disease treated with benznidazole in a highly endemic area of northern Argentina

This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease.