BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.

NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification.

Despite its name, the current diagnosis of acute kidney injury (AKI) still depends on markers of decreased kidney function and not on markers of injury. This results in a delayed diagnosis: AKI is diagnosed based on serum creatinine criteria only when the severity of injury is enough to decrease glomerular filtration rate. Moreover, by the time AKI is diagnosed, the insult may have already ceased, and even appropriate therapy targeted at the specific insult and its associated pathogenic pathways may no longer be effective. Biomarkers of injury are needed that allow the diagnosis of AKI based on injury criteria. At least three commercially available immunoassays assessing urinary or plasma neutrophil gelatinase-associated lipocalin and urinary tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 ([TIMP2]*[IGFBP7]) (NephroCheck®) have generated promising data regarding prediction and early diagnosis of AKI, although their relative performance may depend on clinical context. Recently, a urinary peptidomics classifier (PeptAKI) was reported to predict AKI better than current biomarkers. Focusing on [TIMP2]*[IGFBP7], the cellular origin of urinary TIMP2 and IGFBP7 remains unclear, especially under the most common predisposing condition for AKI, i.e. chronic kidney disease. We now discuss novel data on the kidney cell expression of TIMP2 and IGFBP7 and its clinical implications.

Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences.

Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH4+) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H+. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.

Solving the riddle of Aguascalientes nephropathy: nephron number, environmental toxins and family clustering.

Aguascalientes, Mexico, has a high incidence and prevalence of advanced chronic kidney disease (CKD). CKD is especially frequent in young people ages 20-40 years in whom the cause of CKD was unknown, although kidney biopsies frequently showed focal segmental glomerulosclerosis (FSGS) and glomerulomegaly. Macias-Diaz et al. have now pursued this lead by screening teenagers in Calvillo, one of the hardest hit municipalities. They uncovered clinical, laboratory, kidney biopsy and exposure findings that define a new entity, Aguascalientes nephropathy, and are consistent with familial exposure to common environmental toxins, potentially consisting of pesticides. They hypothesize that prenatal exposure to these toxins may decrease nephron number. The young age of persons with FSGS would be consistent with a novel environmental toxin introduced more than 50 years ago but not present in the environment before. Key takeaways from this research are the need to screen teenagers for albuminuria, to provide kidney-protective strategies to patients identified as having CKD and for the research community to support Aguascalientes nephrologists and health authorities to unravel the cause and potential solutions for this CKD hotspot. In this regard, the screening approach and the cohort generated by Macias-Diaz et al. represent a giant step forward. The next steps should be to screen younger children for albuminuria and kidney size and to identify the putative toxins.

Aguascalientes: one of the hottest chronic kidney disease (CKD) hotspots in Mexico and a CKD of unknown aetiology mystery to be solved.

In a recent issue of Clinical Kidney Journal (CKJ), Gutierrez-Peña et al. reported a high incidence and prevalence of advanced chronic kidney disease (CKD) in Aguascalientes, Mexico. This contradicts Global Burden of Disease estimates, which should be updated. A key component of this high burden of CKD relates to young people ages 20-40 years in whom the cause of CKD was unknown [CKD of unknown aetiology (CKDu)]. The incidence of kidney replacement therapy in this age group in Aguascalientes is among the highest in the world, second only to Taiwan. However, high-altitude Aguascalientes, with a year-round average temperature of 19°C, does not fit the geography of other CKDu hotspots. Furthermore, kidney biopsies in young people showed a high prevalence of focal segmental glomerulosclerosis. Potential causes of CKDu in Aguascalientes include the genetic background (no evidence, although podocytopathy genes should be explored) and environmental factors. The highest prevalence of CKD was found in Calvillo, known for guava farming. Thus guava itself, known to contain bioactive, potentially nephrotoxic molecules and pesticides, should be explored. Additionally, there are reports of water sources in Aguascalientes contaminated with heavy metals and/or pesticides. These include fluoride (increased levels found in Calvillo drinking water) as well as naturally occurring arsenic, among others. Fluoride may accumulate in bone and cause kidney disease years later, and maternal exposure to excess fluoride may cause kidney disease in offspring. We propose a research agenda to clarify the cause of CKDu in Aguascalientes that should involve international funders. The need for urgent action to identify and stem the cause of the high incidence of CKD extends to other CKD hotspots in Mexico, including Tierra Blanca in Veracruz and Poncitlan in Jalisco.

¿Es adecuada la diálisis peritoneal para pacientes mayores de 65 años? Estudio multicéntrico prospectivo / Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study

Escenario: La prevalencia de enfermedad renal crónica (ERC) aumenta en población mayor de 65años y asocia morbilidad, dependencia y fragilidad. La diálisis peritoneal (DP) se ha considerado una técnica de paciente joven y vida activa. Hipótesis: La DP puede ser adecuada en pacientes de edad avanzada. Buscamos resultados desfavorables que contravengan esta hipótesis. Objetivo: Describir el tratamiento con DP en mayores de 65años, evaluar su evolución clínica comparada con los menores de 65 e identificar áreas de mejora asistencial. Estudio: Prospectivo, observacional y multicéntrico en incidentes en DP, seguimiento hasta evento o fin del estudio (ene-2003 a ene-2018).Resultados: Se incluyen 2.435 pacientes; el 31,9% (777) eran mayores de 65 años. El tiempo medio de seguimiento fue de 2,1años para ambos grupos. El grupo de edad avanzada era 25años mayor, con más comorbilidad: diabetes (29,5% vs. 17,2%; p<0,001), evento CV previo (34,5% vs. 14,0%; p<0,001) e índice de Charlson sin edad (3,8 vs. 3,0; p<0,001). No encontramos diferencias en cumplimiento de objetivos intermedios de eficacia de DP, control de anemia o hipertensión durante el seguimiento. La tasa de peritonitis fue mayor en la cohorte mayor de 65años (0,65 vs. 0,45 episodios/paciente-año; p<0,001), aunque la distribución gérmenes, tasa de ingreso y evolución final fue similar en ambos grupos. Lógicamente, registramos mayor mortalidad en el grupo mayor de 65años (28,4% vs. 9,4%), aunque el tiempo de permanencia en DP fue similar (2,1años). La principal causa de salida fue el trasplante renal en jóvenes (48,3%), mientras que en los pacientes de mayor edad fue el paso a hemodiálisis, principalmente por cansancio de cuidador/autocuidado (20,2%) y no por fallo de la técnica (7,3%). (AU)

Background: Chronic kidney disease (CKD) is increasing in patients older than 65years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. Hypothesis: PD should be offered to patients over 65years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. Objective: To describe PD treatment and outcomes in patients >65years, to compare their results with patients <65years and to identify areas with room for improvement in a real-life study. Study: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. Results: We included 2,435 PD patients, 31.9% were older than 65years; there was a difference of 25years between both groups. Median follow up was 2.1years. Older than 65years group had more comorbidity: Diabetes (29.5% vs 17.2%; p<0.001), previous CV events 34.5% vs 14.0%; p<0.001), Charlson index (3.8 vs 3.0; p<0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65years group (0.65 vs 0.45 episodes/patient/year; p<0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1years). The main cause of PD withdrawal was transplant in group <65years (48.3%) and transfer to HD in group >65years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). (AU)

Development and internal validation of a prediction model for hospital-acquired acute kidney injury.

BACKGROUND: Predictive models and clinical risk scores for hospital-acquired acute kidney injury (AKI) are mainly focused on critical and surgical patients. We have used the electronic clinical records from a tertiary care general hospital to develop a risk score for new-onset AKI in general inpatients that can be estimated automatically from clinical records. METHODS: A total of 47 466 patients met inclusion criteria within a 2-year period. Of these, 2385 (5.0%) developed hospital-acquired AKI. Step-wise regression modelling and Bayesian model averaging were used to develop the Madrid Acute Kidney Injury Prediction Score (MAKIPS), which contains 23 variables, all obtainable automatically from electronic clinical records at admission. Bootstrap resampling was employed for internal validation. To optimize calibration, a penalized logistic regression model was estimated by the least absolute shrinkage and selection operator (lasso) method of coefficient shrinkage after estimation. RESULTS: The area under the curve of the receiver operating characteristic curve of the MAKIPS score to predict hospital-acquired AKI at admission was 0.811. Among individual variables, the highest odds ratios, all >2.5, for hospital-acquired AKI were conferred by abdominal, cardiovascular or urological surgery followed by congestive heart failure. An online tool (http://www.bioestadistica.net/MAKIPS.aspx) will facilitate validation in other hospital environments. CONCLUSIONS: MAKIPS is a new risk score to predict the risk of hospital-acquired AKI, based on variables present at admission in the electronic clinical records. This may help to identify patients who require specific monitoring because of a high risk of AKI.

Is peritoneal dialysis suitable technique CKD patients over 65 years? A prospective multicenter study.

BACKGROUND: Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. HYPOTHESIS: PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. OBJECTIVE: To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. STUDY: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. RESULTS: We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. CONCLUSION: Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.

Clarifying the concept of chronic kidney disease for non-nephrologists.

Chronic kidney disease (CKD) expands the prior concept of chronic renal insufficiency by including patients with relatively preserved renal function, as assessed by the estimated glomerular filtration rate (eGFR), as even these early CKD stages are associated with an increased risk for all-cause death and cardiovascular death, CKD progression and acute kidney injury. A decreased eGFR (<60 mL/min/1.73 m2) is by itself diagnostic of CKD when persisting for >3 months. However, when eGFR is ≥60 mL/min/1.73 m2, an additional criterion is required to diagnose CKD. In a recent clinical trial published in The New England Journal of Medicine, all 6190 participants were reported to have CKD: 47% had Stages 1 and 2 CKD and 53% had Stage 3 CKD. This illustrates a widespread misunderstanding of the concept of CKD. Moreover, CKD categories in this study were assigned based on the estimated creatinine clearance. Since both estimated creatinine clearance and creatinine clearance overestimate eGFR, this illustrates another frequent misunderstanding: equating GFR with creatinine clearance. In this commentary, we clarify the concept of CKD and of CKD categories for non-nephrologists. Assigning a diagnosis of CKD to a patient with normal renal function and absence of other evidence of CKD may have negative consequences for the individual (e.g. insurance and others) as well as for the medical community at large by creating confusion about the concept.

Meso-American nephropathy: what we have learned about the potential genetic influence on chronic kidney disease development.

Chronic kidney disease of unknown aetiology (CKDu) refers to the epidemic level of incidence of CKD in several low- and middle-income countries, usually near the equator, for which the aetiology has not been identified. CKDu represents a form of CKD hotspot, defined as a country, region, community or ethnicity with a higher than average incidence of CKD. In terms of the number of persons affected, the so-called hypertensive nephropathy of African Americans probably represents the largest CKD hotspot, which is largely driven by variants of the APOL1 gene, questioning the very existence of hypertensive nephropathy and illustrating how kidney disease driven by genetic predisposition may underlie some forms of hypertension. For CKDu, hard physical work leading to dehydration (the first global warming-related disease?) and local toxins are leading aetiological candidates. Meso-American nephropathy is probably the best-characterized CKDu. In this issue of CKJ, a systematic review and meta-analysis by Gonzalez et al. identified positive associations between Meso-American nephropathy and male gender, family history of CKD, high water intake and lowland altitude. We now discuss the potential relationship of family history to genetic predisposition and how a better understanding of CKDu may help advance the aetiological characterization of the nearly 50% of end-stage renal disease patients worldwide that have no known cause for CKD or have been assigned non-specific diagnoses.

Designing a Method with Physician Participation to Assess and Improve Quality of Healthcare in Otolaryngology.

OBJECTIVE: Patient choice of healthcare centers to be treated for specific diseases is compromised by the low accessibility of understandable information. Physicians are rarely involved in healthcare quality assessment, despite their potentially valuable input. The purpose of this study was to develop a methodology for evaluating the quality of care that specifically incorporates advice from medical specialists and provides accessible information for patients in search of high-quality healthcare. MATERIALS AND METHODS: A pilot Delphi study was conducted among 28 Spanish otolaryngology experts, seeking their opinion on the quality-of-care indicators and on their ability to recommend the most suitable department for the treatment of specific otolaryngologic diseases. RESULTS: The average acceptance rate was 91.9% for quality-of-care indicator and 96.5% for the resources needed for improving the quality of care. Furthermore, 93% experts reported that patients frequently ask for physician advice on which center provides better care for a specific disease, 92.6% experts believe they could recommend the best centers for specific otolaryngologic diseases, and 80% experts agreed that expert opinion on the quality of care offered by different centers would be a valuable addition to quality-of-care assessment. CONCLUSION: The incorporation of physician advice into healthcare quality assessment may improve the usefulness of healthcare quality indicators for patients. Assessment tools incorporating physician advice should be developed and validated.

Inflammatory Cytokines as Uremic Toxins: "Ni Son Todos Los Que Estan, Ni Estan Todos Los Que Son".

Chronic kidney disease is among the fastest growing causes of death worldwide. An increased risk of all-cause and cardiovascular death is thought to depend on the accumulation of uremic toxins when glomerular filtration rate falls. In addition, the circulating levels of several markers of inflammation predict mortality in patients with chronic kidney disease. Indeed, a number of cytokines are listed in databases of uremic toxins and uremic retention solutes. They include inflammatory cytokines (IL-1ß, IL-18, IL-6, TNFα), chemokines (IL-8), and adipokines (adiponectin, leptin and resistin), as well as anti-inflammatory cytokines (IL-10). We now critically review the cytokines that may be considered uremic toxins. We discuss the rationale to consider them uremic toxins (mechanisms underlying the increased serum levels and evidence supporting their contribution to CKD manifestations), identify gaps in knowledge, discuss potential therapeutic implications to be tested in clinical trials in order to make this knowledge useful for the practicing physician, and identify additional cytokines, cytokine receptors and chemokines that may fulfill the criteria to be considered uremic toxins, such as sIL-6R, sTNFR1, sTNFR2, IL-2, CXCL12, CX3CL1 and others. In addition, we suggest that IL-10, leptin, adiponectin and resistin should not be considered uremic toxins toxins based on insufficient or contradictory evidence of an association with adverse outcomes in humans or preclinical data not consistent with a causal association.

Kidney Injury Marker 1 and Neutrophil Gelatinase-Associated Lipocalin in Chronic Kidney Disease.

The current categorization of chronic kidney disease (CKD) is based on biomarkers of the glomerular function (estimated glomerular filtration rate, eGFR) and injury (urinary albumin creatinine ratio, UACR) and provides information on the risk of death and of progression of kidney disease. However, there are gaps in knowledge regarding the risk stratification of elderly patients with eGFR 45-60 ml/min/1.73 m2 and of younger patients with higher eGFR but physiological albuminuria. In this regard, most of the kidney cell mass is composed of tubules. Recent studies have explored whether biomarkers derived from the acute kidney injury literature, which are mainly tubular injury markers, may improve the information provided by eGFR and UACR. We now review the potential role of kidney injury molecule 1 (KIM-1), hepatitis A virus cellular receptor 1, T-cell immunoglobulin and mucin domain-1 and neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin 2 as biomarkers for kidney or cardiovascular outcomes in CKD patients. In general, neither urinary KIM-1 nor urinary NGAL (uNGAL) outperform or add relevant information to eGFR or UACR. However, promising results were obtained for circulating KIM-1 prediction of renal outcomes in type 1 diabetes. Additionally, uNGAL may have some value in non-proteinuric patients and increased values have been observed in persons at risk for Mesoamerican nephropathy. Further studies are warranted in these niche populations.

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.

PCSK9 in diabetic kidney disease.

BACKGROUND: Chronic Kidney Disease (CKD) and, specifically, diabetic kidney disease (DKD)+, 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, since protection offered by statins in CKD patients is not satisfactory. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes hypercholesterolemia and may be targeted therapeutically. Adding anti-PCSK9 agents to standard lipid lowering therapy further reduces the incidence of cardiovascular events. DESIGN: We studied plasma PCSK9 in a cross-sectional study of 134 diabetic kidney disease patients with estimated glomerular filtration rate (eGFR) categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma PCSK9 in this population. RESULTS: Mean±SD plasma PCSK9 levels were 309.8±113.9 ng/ml. Plasma PCSK9 was not influenced by eGFR or albuminuria, but was higher in patients on lipid lowering therapy. In univariate analysis, plasma PCSK9 showed a significant positive correlation with serum total iron binding capacity, vitamin E, plasma renin and phosphaturia, and there was a trend towards a positive correlation with total serum cholesterol. In multivariate models, only therapy with fibrate and statin, and renin remained independently correlated with plasma PCSK9. However, multivariate models explained very little of the PCSK9 variability. CONCLUSIONS: In DKD, therapy with lipid lowering drugs and specially the fibrate/statin combination were independently associated with higher PCSK9 levels. The biomarker potential of PCSK9 levels to identify DKD patients that may benefit from anti-PCSK9 strategies should be studied.

Targeting inflammation in diabetic kidney disease: early clinical trials.

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-1ß antibody gevokizumab in 2015 will postpone the evaluation of therapies targeting inflammatory cytokines.

Small vessel microembolization and acute glomerulonephritis following infection of aesthetic filler implants.

BACKGROUND: The systemic consequences of esthetic filler injections are poorly understood. CASE PRESENTATION: We report a patient with a past history of subcutaneous injection of aesthetic filler material in the lower legs, who presented with post-infectious glomerulonephritis following necrotic leg ulcers at the injection site. Kidney biopsy revealed the presence of translucent, non-birefringent microspherical bodies compatible with polymethylmetacrylate (PMMA) microspheres in some capillary lumens. This had not previously been described. PMMA is a biphasic aesthetical filler composed of polymethylmetacrylate microspheres suspended in a biodegradable bovine collagen carrier. The solid phase (PMMA microspheres) persists in tissues for years. Although PMMA was thought to not disseminate systemically, tissue necrosis may have favored systemic dissemination of the microspheres, although entry in the circulation and microembolization at the time of administration cannot be ruled out. CONCLUSIONS: In conclusion, aesthetic filler implants may cause microembolization into small vessels. Recognition of the characteristic morphology may expedite diagnosis and avoid unnecessary further testing.

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-1ß 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.

Designing drugs that combat kidney damage.

INTRODUCTION: Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority. AREAS COVERED: The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials. EXPERT OPINION: Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI.

Translational value of animal models of kidney failure.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia-reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti-phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future.