A systematic review and meta-analysis of the evidence on inflammation in depressive illness and symptoms in chronic and end-stage kidney disease.

BACKGROUND: Depression affects approximately 27% of adults with chronic kidney disease (CKD) and end-stage kidney failure (ESKF). Depression in this population is associated with impaired quality of life and increased mortality. The extent of inflammation and the impact on depression in CKD/ESKF is yet to be established. Through a systematic literature review and meta-analysis, we aim to understand the relationship between depression and inflammation in CKD/ESKF patients. METHODS: We searched nine electronic databases for published studies until January 2022. Titles and abstracts were screened against inclusion and exclusion criteria. Data extraction and study quality assessment was carried out independently by two reviewers. A meta-analysis was carried out where appropriate; otherwise a narrative review of studies was completed. RESULTS: Sixty studies met our inclusion criteria and entered the review (9481 patients included in meta-analysis). Meta-analysis of cross-sectional associations revealed significantly higher levels of pro-inflammatory biomarkers; C-reactive protein; Interleukin 6 (IL-6) and tumour necrosis factor-alpha in patients with depressive symptoms (DS) compared to patients without DS. Significantly lower levels of anti-inflammatory cytokine IL-10 were found in patients with DS compared to patients without DS. Considerable heterogeneity was detected in the analysis for most inflammatory markers. CONCLUSION: We found evidence for an association of higher levels of pro-inflammatory and lower anti-inflammatory cytokines and DS in patients with CKD/ESKF. Clinical trials are needed to investigate whether anti-inflammatory therapies will be effective in the prevention and treatment of DS in these patients with multiple comorbidities.

Investigating inflammation in depression in the chronically ill: Theoretical model and perspectives.

BACKGROUND: Inflammation is a risk factor for chronic physical illnesses. Evidence is building that inflammation is also a risk factor for mental illnesses making inflammation a common mechanism which could explain the high comorbidity between mental and physical illnesses. METHODS: Based on a systematic search, a review on factors associated with inflammation in the depressed chronically ill has been conducted. Relevant articles have been selected according to the methodological considerations (scope, sample size, type of analysis and bias). RESULTS: Five categories of factors mediate the association between chronic physical and mental illnesses: (1) social-demographic factors, (2) social-economic background, (3) adverse health behaviours, (4) psychological stress and (5) genetics. Psychological therapies and medication also moderate this association. A theoretical model of the interplay between inflammation, depression and chronic physical illness is then presented. DISCUSSION: Inflammation contribute to both chronic physical and mental illnesses. These conclusions support future advances in clinical and research practice, as well as training and education.

Cardiac metabolic remodelling in chronic kidney disease.

Chronic kidney disease (CKD) affects millions of people globally and, for most patients, the risk of developing cardiovascular disease is higher than that of progression to kidney failure. Moreover, mortality owing to cardiovascular complications in patients with CKD is markedly higher than in matched individuals from the general population. This mortality was traditionally thought to be driven by coronary heart disease but >75% of patients with CKD have left ventricular hypertrophy, which contributes to mortality, particularly sudden cardiac death. The aetiology of cardiac complications in CKD is multifactorial. In addition to haemodynamic overload, uraemic toxin accumulation and altered ion homeostasis, which are known to underlie left ventricular hypertrophy in CKD and drive cardiac dysfunction, we examine the role of myocardial metabolic remodelling in CKD. Uraemic cardiomyopathy is characterized by myriad cardiac metabolic maladaptations, including altered mitochondrial function, changes in myocardial substrate utilization, altered metabolic transporter function and expression, and impaired insulin response and phosphoinositide-3 kinase-AKT signalling, which collectively lead to impaired cardiac energetics. Interestingly, none of the standard treatments used to treat CKD target the metabolism of the uraemic heart directly. An improved understanding of the cardiac metabolic perturbations that occur in CKD might allow the development of novel treatments for uraemic cardiomyopathy.

NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes.

BACKGROUND: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. DESIGN: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. SUMMARY: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Response to Vaccination Against SARS-CoV-2 in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Involvement.

BACKGROUND: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) present with multisystem disease including renal impairment. The treatment for AAV involves a high burden of immunosuppression. Patients with renal involvement are treated especially intensively. As a result, we identified these patients as being potentially at high risk of failure to seroconvert to COVID-19 vaccination. METHODS: We collected data on seroconversion response rates to COVID-19 vaccination in a multi-ethnic cohort of patients with AAV and renal involvement treated at a busy tertiary nephrology centre as part of a retrospective review of patient notes. Blood samples were taken following vaccination with either Pfizer or Astra-Zeneca COVID-19 vaccines and median fluorescence intensity was measured using the validated MULTICOV-Ab Magnetic LuminexⓇ Assay. We also evaluated whether seroconversion was affected by immunosuppression regimen. RESULTS: 81 patients were included. The mean age was 62, and there were 49 (60%) females. 55 patients had a blood test after the first dose; 46 after the second dose. Patients were in remission with a median BVAS of 0 (IQR 2). Seroconversion after the first dose with either vaccine was 35/55 (63.6%). After the second it was 38/46 (82.6%). Subgroup analyses revealed a trend to impaired seroconversion in non-white versus white patients (77.8 vs. 81.7% (p = 0.69) after the first dose of vaccine and in those treated with Rituximab in the last 12 months (73.3 vs. 87.1%, p = 0.41). CONCLUSIONS: These data offer real-world evidence of lower seroconversion in response to vaccination with one dose in patients with AAV and renal involvement than the general UK population. After two doses, seroconversion is in line with national data. These data provide a rationale for hospital-led identification of patients most at risk of COVID-19 and underscore the importance of local connexions between hospitals and their communities. These data provide further support for targeting booster vaccination programmes to vulnerable patient cohorts. They add to the growing evidence of reduced seroconversion in response to vaccination in patients with renal disease of any cause.

Novel Homozygous FAN1 Mutation in a Familial Case of Karyomegalic Interstitial Nephritis.

Karyomegalic interstitial nephritis (KIN) is a rare genetic kidney disease associated with a mutation in FAN1 gene and is often underdiagnosed. The histomorphology demonstrates chronic interstitial nephritis with tubular epithelial cells showing bizarre enlarged nuclei. We present a case report of a 47-year-old multiparous South-Indian woman presenting with bilateral pitting pedal oedema and mild hypertension. At the time of presentation, her serum creatinine was 1.52 mg/dL and urine analysis showed mild proteinuria. Kidney biopsy showed features of tubular injury with bizarre enlarged nuclei and focal mild chronic tubulointerstitial nephritis. Immunohistochemistry was negative for cytomegalovirus (CMV) Ag and SV40 Ag. Real-time polymerase chain reaction (PCR) done for CMV and BK virus genomes was negative. Relevant family history was that her older brother was also diagnosed with kidney failure and is on renal replacement therapy. Genetic analysis for FAN1 gene of the proband and her sibling showed two rare mutations of the FAN1 gene in the exon 4, of which, one is non-synonymous mutation and the other is a stop-gain mutation in the proband. This case illustrates a rare presentation of karyomegalic interstitial nephritis in siblings with previous unknown FAN1 gene mutations.

HEROIC: a 5-year observational cohort study aimed at identifying novel factors that drive diabetic kidney disease: rationale and study protocol.

INTRODUCTION: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease worldwide and a major cause of premature mortality in diabetes mellitus (DM). While improvements in care have reduced the incidence of kidney disease among those with DM, the increasing prevalence of DM means that the number of patients worldwide with DKD is increasing. Improved understanding of the biology of DKD and identification of novel therapeutic targets may lead to new treatments. A major challenge to progress has been the heterogeneity of the DKD phenotype and renal progression. To investigate the heterogeneity of DKD we have set up The East and North London Diabetes Cohort (HEROIC) Study, a secondary care-based, multiethnic observational study of patients with biopsy-proven DKD. Our primary objective is to identify histological features of DKD associated with kidney endpoints in a cohort of patients diagnosed with type 1 and type 2 DM, proteinuria and kidney impairment. METHODS AND ANALYSIS: HEROIC is a longitudinal observational study that aims to recruit 500 patients with DKD at high-risk of renal and cardiovascular events. Demographic, clinical and laboratory data will be collected and assessed annually for 5 years. Renal biopsy tissue will be collected and archived at recruitment. Blood and urine samples will be collected at baseline and during annual follow-up visits. Measured glomerular filtration rate (GFR), echocardiography, retinal optical coherence tomography angiography and kidney and cardiac MRI will be performed at baseline and twice more during follow-up. The study is 90% powered to detect an association between key histological and imaging parameters and a composite of death, renal replacement therapy or a 30% decline in estimated GFR. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Bloomsbury Research Ethics Committee (REC 18-LO-1921). Any patient identifiable data will be stored on a password-protected National Health Services N3 network with full audit trail. Anonymised imaging data will be stored in a ISO27001-certificated data warehouse.Results will be reported through peer-reviewed manuscripts and conferences and disseminated to participants, patients and the public using web-based and social media engagement tools as well as through public events.

Tuberculosis in the 21st century: A narrative review.

Sadly, despite the discovery of the tuberculosis bacillus over a century ago by Robert Koch, tuberculosis remains a major killer and modern day plague. Progress in the eradication of tuberculosis has been very slow and will require determined efforts on multiple fronts to make substantial inroads to lower the currently stagnant incidence of around 2% globally.

Systematic Review and the External Validity of Randomized Controlled Trials in Lupus Nephritis.

INTRODUCTION: Randomized controlled trials (RCTs) are considered the gold standard for assessing treatment efficacy. However, sampling bias can affect the generalization of results to routine clinical practice. Here we assessed whether patients with lupus nephritis (LN) seen in routine clinical practice would have satisfied entry criteria to the major published RCTs in LN. METHODS: A systematic literature search from January 1974 to May 2015 was carried out, identifying all RCTs investigating LN induction treatment. Patients diagnosed with proliferative or membranous LN between 1995 and 2013 were identified from the Barts Lupus Centre database; baseline characteristics were compared with each RCT's entry criteria to assess hypothetical inclusion or exclusion. RESULTS: Of 363 articles, 33 RCTs met inclusion criteria. Of 137 patients newly diagnosed with LN (111 with proliferative/mixed proliferative and 26 with pure membranous LN), 32% would have been excluded from RCT entry (range 8%-73%). The main reasons for exclusion would have been too severe disease, too mild disease, or prior immunosuppressant use, which were exclusion criteria in 26, 20, and 22 RCTs, respectively. A total of 27 patients with LN (20%) were re-biopsied due to flare; 68% of these would have been ineligible to enter RCTs. CONCLUSION: Published RCTs do not truly reflect the heterogeneity of patients with LN in routine practice at our lupus center. The external validity of RCTs could be improved by including more representative patient cohorts. RCTs should be used as a guide but consideration should be given to similarities between individual patients and the characteristics of the trial cohorts before treatment decisions being made.

Ethnic/Race Diversity and Diabetic Kidney Disease.

Ethnicity and race are often used interchangeably in the literature. However, the traditional definition of race and ethnicity is related to biological (bone structure and skin, hair, or eye color) and sociological factors (nationality, regional culture, ancestry, and language) respectively. Diabetes mellitus (DM) is a huge global public health problem. As the number of individuals with Type 2 DM grows, the prevalence of diabetic kidney disease (DKD), which is one of the most serious complications, is expected to rise sharply. Many ethnic and racial groups have a greater risk of developing DM and its associated macro and micro-vascular complications.

Evaluating ethnic differences in the prescription of NSAIDs for chronic kidney disease: a cross-sectional survey of patients in general practice.

BACKGROUND: The public health burden of chronic kidney disease (CKD) and end-stage kidney disease is a national priority and is the subject of recent guidelines. In the UK, ethnic minority groups are over-represented in the renal replacement population (17.8%) compared with the white population (11%). AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) are a preventable cause of renal damage. Previous studies suggest a prescribing prevalence between 9% and 36% among those with CKD, but have not examined differences by ethnic group. DESIGN AND SETTING: Cross-sectional survey of 12 011 patients with identified CKD (stages 3-5) in the three PCTs of Tower Hamlets, Hackney, and Newham. METHOD: Assessment of NSAID prescribing rates in a multi-ethnic, socially-deprived population, using descriptive and multivariate analysis. RESULTS: NSAIDs were prescribed for 11.1% of patients with CKD in the year prior to November 2012. Prescribing rates decreased stepwise by stage of renal impairment. Using daily defined dosages this study shows that in comparison with white groups both South Asian and black groups are much less likely to be in the top decile of NSAID prescribing, hence the overall prescribing load will be less: (odds ratio [OR] for South Asians = 0.34, 95% confidence interval [CI] = 0.22 to 0.54, OR for black groups = 0.34, 95% CI = 0.19 to 0.63). CONCLUSION: National rates of NSAID prescribing continue to rise, and over-the-counter sales remain unmonitored, despite longstanding concerns about renal outcomes. Prescribing patterns indicate that GPs reduce prescribing as CKD progresses. Differential use of NSAIDs by ethnic group is unlikely to contribute to the high rates of end-stage kidney disease in ethnic minority groups.

Elevated hepatic 11ß-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia.

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11ß-Hydroxysteroid dehydrogenase type 1 (11ßHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11ßHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11ßHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11ßHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11ßHSD1(-/-) mice and rats treated with a specific 11ßHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11ßHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11ßHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Endovascular repair of symptomatic hemodialysis access graft pseudoaneurysms.

AIM: Repeated needle punctures of arteriovenous hemodialysis grafts can lead to the development of pseudoaneurysms. As they enlarge, graft pseudoaneurysms are associated with significant morbidity and require treatment. We present our single-center experience using stent grafts in selected patients to exclude symptomatic hemodialysis graft pseudoaneurysms. MATERIALS AND METHODS: Between March 2007 and December 2010, 11 consecutive patients (7 men and 4 women, mean age 57 years) underwent percutaneous endovascular repair of symptomatic hemodialysis access graft pseudoaneurysms. Indications for treatment were rapidly enlarging pseudoaneurysm in 5 patients, high venous pressures, limb edema and pseudoaneurysm in 3, skin breakdown over the pseudoaneurysm site in 2 and acute rupture and bleeding in 1 patient. No patient was lost to follow-up. RESULTS: Technical success across the 11 patients was 90.9%. The patient who presented with rupture required ligation of the access due to continuous bleeding after stent graft insertion. Balloon angioplasty of a separate hemodynamically significant stenosis at the time of stent graft insertion was performed in 7 of 11 (63.6%) patients. The primary access patency rates were 72.7% (95% CI of 0.390-0.939) at 3 months and 36.4% (95% CI 0.109-0.692) at 6 months. Secondary access patency rates were 72.7% at 6 months (95% CI 0.233-0.832). There were no procedure-related complications. Mean follow-up was 9 months (range 2-29 months). CONCLUSIONS: Endovascular treatment of symptomatic hemodialysis graft pseudoaneurysms is safe and effective with similar patency rates to surgical approaches. Importantly, this approach allows aggressive management of associated access circuit stenoses at the same time and avoids interval tunneled dialysis line insertion.

Lessons learned from peginesatide in the treatment of anemia associated with chronic kidney disease in patients on dialysis.

Peginesatide is the newest erythropoietin-stimulating agent (ESA) in the quest for the ideal treatment of anemia in chronic kidney disease (CKD) patients. Reduced frequency of administration along with a possibly lower cost as a result of simpler manufacturing techniques compared with other available agents makes peginesatide a highly desirable product in the competitive ESA market. Peginesatide is noninferior to the other ESAs, and has a good safety profile in patients on hemodialysis. The higher rates of adverse cardiovascular events reported in CKD patients not on dialysis in the recent Phase III studies require further, better planned, studies. Peginesatide had to be withdrawn from the market in the US after some reports of hypersensitivity reactions to the drug. This is a setback, but the scientific advances gained as a result of this product development can be used to develop other, newer products.

Is lack of suitable housing a barrier to home-based dialysis therapy for patients with end-stage renal disease? A cohort study.

OBJECTIVE: To determine whether inadequate housing is the main barrier to the provision of home dialysis treatment. DESIGN: Prospective observational study. PARTICIPANTS: All patients attending a predialysis clinic between 2006 and 2009 deemed medically suitable for home dialysis and not active on the preemptive transplant list. SETTING: A predialysis clinic in a London teaching hospital. MAIN OUTCOME MEASURE: Assessment of patient's accommodation for suitability for home-based dialysis using departmental guidelines and the Government's Housing Health and Safety Rating System regulations 2005. RESULTS: A lack of adequate housing prohibited the provision of home haemodialysis to all but one of these patients. Moreover, only 29% of homes assessed were suitable for peritoneal dialysis, despite the lower spatial demands of this form of renal replacement therapy. In addition to the specific requirements of dialysis, we also found that only 33% of the homes visited fulfilled the minimum standard of housing as defined in the Government's Decent Homes Standard, with multiple specific hazards identified across the properties. CONCLUSIONS: This study illustrates that the lack of suitable housing is a major barrier to the provision of home-based dialysis and underscores the need for this to be addressed urgently at both the central government and local authority levels. We suggest that it should be considered as a major priority to rehouse medically suitable patients with a view to enabling home-based therapy.

The relationship of ethnicity to the prevalence and management of hypertension and associated chronic kidney disease.

BACKGROUND: The effect of ethnicity on the prevalence and management of hypertension and associated chronic kidney (CKD) disease in the UK is unknown. METHODS: We performed a cross sectional study of 49,203 adults with hypertension to establish the prevalence and management of hypertension and associated CKD by ethnicity. Routinely collected data from general practice hypertension registers in 148 practices in London between 1/1/07 and 31/3/08 were analysed. RESULTS: The crude prevalence of hypertension was 9.5%, and by ethnicity was 8.2% for White, 11.3% for South Asian and 11.1% for Black groups. The prevalence of CKD stages 3-5 among those with hypertension was 22%. Stage 3 CKD was less prevalent in South Asian groups (OR 0.77, 95% CI 0.67 - 0.88) compared to Whites (reference population) with Black groups having similar rates to Whites. The prevalence of severe CKD (stages 4-5) was higher in the South Asian group (OR 1.53, 95% CI 1.17 - 2.0) compared to Whites, but did not differ between Black and White groups. In the whole hypertension cohort, achievement of target blood pressure (< 140/90 mmHg) was better in South Asian (OR 1.43, 95% CI 1.28 - 1.60) and worse in Black groups (OR 0.79, 95% CI 0.74 - 0.84) compared to White patients. Hypertensive medication was prescribed unequally among ethnic groups for any degree of blood pressure control. CONCLUSIONS: Significant variations exist in the prevalence of hypertension and associated CKD and its management between the major ethnic groups. Among those with CKD less than 50% were treated to a target BP of ≤ 130/80 mmHg. Rates of ACE-I/ARB prescribing for those with CKD were less than optimal, with the lowest rates (58.5%) among Black groups.

New flow cytometric technique for the evaluation of circulating endothelial progenitor cell levels in various disease groups.

Circulating endothelial progenitor cells (EPC) localise to sites of ischaemia and play a role in vascular repair and re-endothelialisation of injured blood vessels. Low levels of EPCs are associated with cardiovascular disease (CVD) in the general population. It is not clear at present whether and how the numbers of circulating EPCs vary in diseases other than CVD. We have enumerated EPCs by the flow cytometric analysis of whole blood by using a novel cocktail of monoclonal antibodies. This consisted of CD2FITC, CD13FITC and CD22FITC to eliminate non-progenitor cells and VEGFR2PE and CD133-streptavidin-PeCy7 to include only EPCs. We analysed 250 patients with varying stages of uraemia, 36 patients with inflammatory bowel disease (IBD) and 9 patients with acute respiratory distress syndrome and compared this to 74 healthy controls. Using flow cytometry we were able to measure the circulating levels of EPCs, with a result available within hours of the sample being obtained. Circulating EPC numbers vary in different patient groups and healthy controls. In uraemic patients, irrespective of disease severity, there are lower numbers of circulating EPC numbers compared to normal controls (46.6+/-3.7 vs. 66.1+/-4.7; p=0.03). This new technique provides a means of monitoring patients and shows a reduction in circulating EPCs in uraemic patients; this abnormality may be a target of novel therapies.