Maria Vanessa Perez-Gomez

Klotho, phosphate and inflammation/ageing in chronic kidney disease

Evidence is emerging for the inflammatory nature of many ageing-associated diseases, including atherosclerosis, vascular calcification, diabetes and chronic kidney disease (CKD), among others. Ageing itself results in chronic low-grade inflammation that promotes end-organ damage. Inflammatory organ damage, in turn, may contribute to inflammation. Recent research has identified the kidney-secreted hormone Klotho as a central player at the ageing-inflammation interface. Thus, systemic or local renal inflammation decreases kidney Klotho expression. Klotho down-regulation may be induced by specific cytokines such as tumour necrosis factor-α or TWEAK through the canonical activation of the inflammatory transcription factor nuclear factor kappa B (NFκB) and, specifically RelA. In addition, inflammatory cytokines lead to the epigenetic inactivation of Klotho transcription. Klotho itself has antioxidant and anti-inflammatory properties and the canonical NFκB component RelA is one of its targets. Klotho is a key regulator of phosphate balance and a role of phosphate in ageing has been shown. However, the potential relationship between phosphate and inflammation requires further clarification. A correct understanding of these interactions may lead to the design of novel therapeutic approaches to CKD and CKD-related inflammatory and ageing features as well as to inflammation/ageing in general.

The Choice of Hemodialysis Membrane Affects Bisphenol A Levels in Blood

Bisphenol A (BPA), a component of some dialysis membranes, accumulates in CKD. Observational studies have linked BPA exposure to kidney and cardiovascular injury in humans, and animal studies have described a causative link. Normal kidneys rapidly excrete BPA, but insufficient excretion may sensitize patients with CKD to adverse the effects of BPA. Using a crossover design, we studied the effect of dialysis with BPA-containing polysulfone or BPA-free polynephron dialyzers on BPA levels in 69 prevalent patients on hemodialysis: 28 patients started on polysulfone dialyzers and were switched to polynephron dialyzers; 41 patients started on polynephron dialyzers and were switched to polysulfone dialyzers. Results were grouped for analysis. Mean BPA levels increased after one hemodialysis session with polysulfone dialyzers but not with polynephron dialyzers. Chronic (3-month) use of polysulfone dialyzers did not significantly increase predialysis serum BPA levels, although a trend toward increase was detected (from 48.8±6.8 to 69.1±10.1 ng/ml). Chronic use of polynephron dialyzers reduced predialysis serum BPA (from 70.6±8.4 to 47.1±7.5 ng/ml, P<0.05). Intracellular BPA in PBMCs increased after chronic hemodialysis with polysulfone dialyzers (from 0.039±0.002 to 0.043±0.001 ng/10(6) cells, P<0.01), but decreased with polynephron dialyzers (from 0.045±0.001 to 0.036±0.001 ng/10(6) cells, P<0.01). Furthermore, chronic hemodialysis with polysulfone dialyzers increased oxidative stress in PBMCs and inflammatory marker concentrations in circulation. In vitro, polysulfone membranes released significantly more BPA into the culture medium and induced more cytokine production in cultured PBMCs than did polynephron membranes. In conclusion, dialyzer BPA content may contribute to BPA burden in patients on hemodialysis.

Targeting inflammation in diabetic kidney disease: early clinical trials

ABSTRACT Introduction: The age-standardized death rate from diabetic kidney disease increased by 106% from 1990 to 2013, indicating that novel therapeutic approaches are needed, in addition to the renin-angiotensin system (RAS) blockers currently in use. Clinical trial results of anti-fibrotic therapy have been disappointing. However, promising anti-inflammatory drugs are currently on phase 1 and 2 randomized controlled trials. Areas covered: The authors review the preclinical, phase 1 and 2 clinical trial information of drugs tested for diabetic kidney disease that directly target inflammation as a main or key mode of action. Agents mainly targeting other pathways, such as endothelin receptor or mineralocorticoid receptor blockers and vitamin D receptor activators are not discussed. Expert opinion: Agents targeting inflammation have shown promising results in the treatment of diabetic kidney disease when added on top of RAS blockade. The success of pentoxifylline in open label trials supports the concept of targeting inflammation. In early clinical trials, the pentoxifylline derivative CTP-499, the CCR2 inhibitor CCX140-B, the CCL2 inhibitor emapticap pegol and the JAK1/JAK2 inhibitor baricitinib were the most promising drugs for diabetic kidney disease. The termination of trials testing the anti-IL-1β antibody gevokizumab in 2015 will postpone the evaluation of therapies targeting inflammatory cytokines.

Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.

Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing.

There are no pathophysiolgical therapeutic approaches to acute kidney injury (AKI) and the mortality remains high. In addition chronic kidney disease (CKD) predisposes to AKI and AKI contributes to progression of CKD. Recently a transcriptomics approach unveiled a relationship between AKI, inflammation and the regulation of ageing. A transcriptomics analysis of experimental AKI revealed increased kidney expression of Fn14 and transmembrane chemokine CXCL16, as well as a decreased expression of the kidney-secreted anti-ageing hormone Klotho. Fn14 is the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily. In AKI kidneys there was a positive correlation between Fn14 and CXCL16 mRNA expression and an inverse correlation between Fn14 and Klotho mRNA. Tubular cells were the site of Fn14, CXCL16 and Klotho expression in vivo. Research on the relationships between these three molecules disclosed that TWEAK activation of Fn14 promoted inflammation through secretion of chemokines such as CXL16 in tubular cells in culture and in vivo. Furthermore, TWEAK activation of Fn14 decreased expression of Klotho mRNA and protein in culture and in vivo. Interestingly, both TWEAK activation of CXCL16 mRNA transcription and suppression of Klotho mRNA transcription were mediated by the NFκB transcription factor. In conclusion, TWEAK engagement of Fn14 is a central event promoting NFκB-mediated activation of inflammation pathways and suppression of anti-inflammatory/anti-ageing pathways. This information may influence future therapeutic approaches to AKI and inflammation/aging.

Nutrients Turned into Toxins: Microbiota Modulation of Nutrient Properties in Chronic Kidney Disease

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of death. Some uremic toxins are ingested with the diet, such as phosphate and star fruit-derived caramboxin. Others result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves. These nutrients include l-carnitine, choline/phosphatidylcholine, tryptophan and tyrosine, which are also sold over-the-counter as nutritional supplements. Physicians and patients alike should be aware that, in CKD patients, the use of these supplements may lead to potentially toxic effects. Unfortunately, most patients with CKD are not aware of their condition. Some of the dietary components may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins, such as trimethylamine N-Oxide (TMAO), p-cresyl sulfate, indoxyl sulfate and indole-3 acetic acid. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of death and cardiovascular disease and there is evidence that this association may be causal. Future developments may include maneuvers to modify gut processing or absorption of these nutrients or derivatives to improve CKD patient outcomes.

Combination use of medicines from two classes of renin–angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function

European and United States regulatory agencies recently issued warnings against the use of dual renin–angiotensin system (RAS) blockade therapy through the combined use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aliskiren in any patient, based on absence of benefit for most patients and increased risk of hyperkalemia, hypotension, and renal failure. Special emphasis was made not to use these combinations in patients with diabetic nephropathy. The door was left open to therapy individualization, especially for patients with heart failure, when the combined use of an ARB and ACEI is considered absolutely essential, although renal function, electrolytes and blood pressure should be closely monitored. Mineralocorticoid receptor antagonists were not affected by this warning despite increased risk of hyperkalemia. We now critically review the risks associated with dual RAS blockade and answer the following questions: What safety issues are associated with dual RAS blockade? Can the safety record of dual RAS blockade be improved? Is it worth trying to improve the safety record of dual RAS blockade based on the potential benefits of the combination? Is dual RAS blockade dead? What is the role of mineralocorticoid antagonists in combination with other RAS blocking agents: RAAS blockade?

Circulating CXCL16 in Diabetic Kidney Disease.

Background/Aims: Chronic kidney disease and, specifically, diabetic kidney disease, is among the fastest increasing causes of death worldwide. A better understanding of the factors contributing to the high mortality may help design novel monitoring and therapeutic approaches. CXCL16 is both a cholesterol receptor and a chemokine with a potential role in vascular injury and inflammation. We aimed at identifying predictors of circulating CXCL16 levels in diabetic patients with chronic kidney disease. Methods: We have now studied plasma CXCL16 in 134 European patients with diabetic kidney disease with estimated glomerular filtration rate (eGFR) categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma CXCL16 in this population. Results: Plasma CXCL16 levels were 4.0±0.9 ng/ml. Plasma CXCL16 increased with increasing eGFR category from G1 to G4 (that is, with decreasing eGFR values) and with increasing albuminuria category. Plasma CXCL16 was higher in patients with prior cardiovascular disease (4.33±1.03 vs 3.88±0.86 ng/ml; p=0.013). In multivariate analysis, eGFR and serum albumin had an independent and significant negative correlation with plasma CXCL16. Conclusion: In diabetic kidney disease patients, GFR and serum albumin independently predicted plasma CXCL16 levels.

Haemodialysate: long neglected, difficult to optimize, may modify hard outcomes.

In two recent CKJ reviews, experts (Basile and Lomonte and Locatelli et al.) have reviewed haemodialysate composition. A long-neglected issue, observational studies have associated the composition of haemodialysate to adverse outcomes. However, the scarcity of clinical trial-derived information results in limited guideline recommendations on the issue. Indeed, guidelines have more frequently indicated what not to do rather than what to do. In this setting, expert opinion becomes invaluable. In designing haemodialysate composition, a balance should be struck between the need to correct within a time frame of around 4 hours the electrolyte and water imbalances that take 48 to 72 h to build, with the need for gradual correction of these imbalances. The issue is complicated further by the impact of individual variability in dietary habits, medications and comorbidities. In this regard, a personalized medicine approach to individualization of haemodialysate composition offers the best chance of improving patient outcomes. But how can haemodialysate individualization be achieved, and what clinical trial design will best test the impact of such approaches on patient outcomes?

Modifiable risk factors for increased arterial stiffness in outpatient nephrology.

Arterial stiffness, as measured by pulse wave velocity (PWV), is an independent predictor of cardiovascular events and mortality. Arterial stiffness increases with age. However, modifiable risk factors such as smoking, BP and salt intake also impact on PWV. The finding of modifiable risk factors may lead to the identification of treatable factors, and, thus, is of interest to practicing nephrologist. We have now studied the prevalence and correlates of arterial stiffness, assessed by PWV, in 191 patients from nephrology outpatient clinics in order to identify modifiable risk factors for arterial stiffness that may in the future guide therapeutic decision-making. PWV was above normal levels for age in 85/191 (44.5%) patients. Multivariate analysis showed that advanced age, systolic BP, diabetes mellitus, serum uric acid and calcium polystyrene sulfonate therapy or calcium-containing medication were independent predictors of PWV. A new parameter, Delta above upper limit of normal PWV (Delta PWV) was defined to decrease the weight of age on PWV values. Delta PWV was calculated as (measured PWV) - (upper limit of the age-adjusted PWV values for the general population). Mean±SD Delta PWV was 0.76±1.60 m/sec. In multivariate analysis, systolic blood pressure, active smoking and calcium polystyrene sulfonate therapy remained independent predictors of higher delta PWV, while age, urinary potassium and beta blocker therapy were independent predictors of lower delta PWV. In conclusion, arterial stiffness was frequent in nephrology outpatients. Systolic blood pressure, smoking, serum uric acid, calcium-containing medications, potassium metabolism and non-use of beta blockers are modifiable factors associated with increased arterial stiffness in Nephrology outpatients.