Measuring and Estimating GFR and Treatment Effect in ADPKD Patients: Results and Implications of a Longitudinal Cohort Study

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m2 in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial.

BACKGROUND: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS: The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS: 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION: In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney graft

Prevalence of hypertension and diabetes and coexistence of chronic kidney disease and cardiovascular risk in the population of the Republic of Moldova

In 2005, the International Society of Nephrology (ISN) established the Global Outreach Program (GO) aimed at building a capacity for detecting and managing chronic kidney disease and its complications in low- and middle-income countries. Here we report data from the 2006-2007 screening program (1025 subjects from the general population) in the Republic of Moldova aimed to determine the prevalence of hypertension, diabetes, and their coexistence with microalbuminuria. The likelihood of a serious cardiovascular (CV) event was also estimated. Hypertension and diabetes were very common among screened subjects. The prevalence of microalbuminuria was 16.9% and that of estimated GFR <60 ml/min/1.73 m2 (decreased renal function) was 9.4%. Male gender was associated with an increased prevalence of hypertension and microalbuminuria. Hypertension and diabetes clustered in subjects with microalbuminuria and renal dysfunction. Risk factors such as preobesity/obesity, physical inactivity and smoking were relatively common, even in younger participants. The prevalence of subjects with predicted 10-year CV risk 65 10% was 10.0%. In conclusion, in the Republic of Moldova patients with hypertension and diabetes should be screened for the coexistence of renal abnormalities, with the intention of developing disease-specific health-care interventions with the primary goal to reduce CV morbidity and mortality and prevent renal disease progression to end stage renal disease

Blood pressure and metabolic effects of acetyl-L-carnitine in type 2 diabetes: DIABASI randomized controlled trial

Context: Acetyl-L-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. Objective: To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. Design: After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Setting: Five diabetology units and one clinical research center in Italy. Patients: Two hundred twenty-nine patients with hypertension and dyslipidemic T2D &gt; 40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine &lt; 1.5 mg/ dL. Interventions: Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Outcome and Measures: Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. Results: SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09mmHg vs-3.57mmHg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Conclusions: Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Association between the Perioperative Antioxidative Ability of Platelets and Early Post-Transplant Function of Kidney Allografts: A Pilot Study

BACKGROUND: Recent studies have demonstrated that the actions of platelets may unfavorably influence post-transplant function of organ allografts. In this study, the association between post-transplant graft function and the perioperative activity of platelet antioxidants was examined among kidney recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups. METHODOLOGY/PRINCIPAL FINDINGS: Activities of superoxide dismutase, catalase, glutathione transferase (GST), glutathione peroxidase, and glucose-6-phosphate dehydrogenase (G6P) were determined and levels of glutathione, oxidized glutathione, and isoprostane were measured in blood samples collected immediately before and during the first and fifth minutes of renal allograft reperfusion. Our results demonstrated a significant increase in isoprostane levels in all groups. Interestingly, in DGF patients, significantly lower levels of perioperative activity of catalase (p<0.02) and GST (p<0.02) were observed. Moreover, in our study, the activity of platelet antioxidants was associated with intensity of perioperative oxidative stress. For discriminating SGF/DGF from EGF, sensitivity, specificity, and positive and negative predictive values of platelet antioxidants were 81-91%, 50-58%, 32-37%, and 90-90.5%, respectively. CONCLUSIONS: During renal transplantation, significant changes occur in the activity of platelet antioxidants. These changes seem to be associated with post-transplant graft function and can be potentially used to differentiate between EGF and SGF/DGF. To the best of our knowledge, this is the first study to reveal the potential protective role of platelets in the human transplantation setting

Metabolic stress promotes renal tubular inflammation by triggering the unfolded protein response

The renal epithelium contributes to the development of inflammation during ischemic injury. Ischemia induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). Ischemic tissues generate distress signals and inflammation that activates fibrogenesis and may promote adaptive immunity. Interestingly, the UPR may activate inflammation pathways. Our aim was to test whether the UPR is activated during metabolic stress and mediates a tubular inflammatory response. Glucose deprivation, not hypoxia and amino acids deprivation, activated the UPR in human renal cortical tubular cells in culture. This stress activated NF-κB and promoted the transcription of proinflammatory cytokines and chemokines, including IL-6, IL-8, TNF-α, RANTES and MCP-1. The protein kinase RNA (PKR)-like ER kinase signaling pathway was not required for the induction of inflammation but amplified cytokine. Inositol-requiring enzyme 1 activated NF-κB signaling and was required for the transcription of proinflammatory cytokines and chemokines following metabolic stress. Moreover, acute ischemia activated ER stress and inflammation in rat kidneys. Finally, the ER stress marker GRP78 and NF-κB p65/RelA were coexpressed in human kidney transplants biopsies performed before implantation, suggesting that ER stress activates tubular inflammation in human renal allografts. In conclusion, this study establishes a link between ischemic stress, the activation of the UPR and the generation of a tubular inflammatory response

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world