Insulin Resistance as a Therapeutic Target for Chronic Kidney Disease.

Insulin resistance (IR) is a prevalent metabolic feature in chronic kidney disease (CKD). Postreceptor insulin-signaling defects have been observed in uremia. A decrease in the activity of phosphatidylinositol 3-kinase appears critical in the pathophysiology of CKD-associated IR. Lipotoxicity due to ectopic accumulation of lipid moieties has recently emerged as another mechanism by which CKD and/or associated metabolic disorders may lead to IR through impairment of various insulin-signaling molecules. Metabolic acidosis, anemia, excess of fat mass, inflammation, vitamin D deficiency, adipokine imbalance, physical inactivity, and the accumulation of nitrogenous compounds of uremia all contribute to CKD-associated IR. The clinical impacts of IR in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD. This is why IR may be a therapeutic target in the attempt to improve outcomes in CKD. General measures to improve IR are directed to counteract causal factors. The use of pharmaceutical agents such as inhibitors of the renin-angiotensin system may improve IR in hypertensive and CKD patients. Pioglitazone appears a safe and promising therapeutic agent to reduce IR and uremic-associated abnormalities. However, interventional studies are needed to test if the reduction and/or normalization of IR may actually improve outcomes in these patients.

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.

BACKGROUND: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. METHODS: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. FINDINGS: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. INTERPRETATION: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. FUNDING: UK Medical Research Council, US National Institutes of Health.

The kidney during hibernation and arousal from hibernation. A natural model of organ preservation during cold ischaemia and reperfusion.

BACKGROUND: During hibernation the kidney is in a hypothermic condition where renal blood flow is minimal and urine production is much reduced. Periodical arousal from hibernation is associated with kidney reperfusion at increasing body temperature, and restored urine production rate. METHODS: To assess the degree of structural preservation during such extreme conditions, the kidney cortex was investigated by means of electron microscopy in the dormouse Muscardinus avellanarius during winter hibernation, arousal from hibernation and the summer active period. RESULTS: Results show that the fine structure of the kidney cortex is well preserved during hibernation. In the renal corpuscle, a sign of slight lesion was the focal presence of oedematous endothelial cells and/or podocytes. Proximal convoluted tubule cells showed fully preserved ultrastructure and polarity, and hypertrophic apical endocytic apparatus. Structural changes were associated with increased plasma electrolytes, creatinine and urea nitrogen, and proteinuria. During the process of arousal the fine structure of the kidney cortex was also well maintained. CONCLUSION: These results demonstrate that dormice are able to fully preserve kidney cortex structure under extreme conditions resembling e.g. severe ischaemia or hypothermic organ storage for transplantation, and reperfusion. Elucidation of the mechanisms involved in such a natural model of organ preservation could be relevant to human medicine.

Impact of anti-T cell therapy in the immunogenicity of seasonal influenza vaccine in kidney transplants recipients

1. Mise en perspective de l'étude La grippe est une cause importante de morbidité et de mortalité après la transplantation d'organe. Bien que la principale stratégie de prévention de la grippe après la transplantation d'organes soit l'administration du vaccin antigrippal annuel, l'immunogénicité de ce vaccin chez les greffés d'organe n'est pas optimale. Nous avons effectué une étude prospective pour évaluer l'influence de la thérapie d'induction sur l'immunogénicité du vaccin de la grippe. 2. Méthodes Nous avons comparé la réponse au vaccin de la grippe chez deux groupes de greffés rénaux en fonction de la thérapie d'induction reçu (thymoglobulin vs basiliximab). Le taux des anticorps ont étés mesurés par inhibition de l'hémagglutination (HI). La réponse au vaccin (taux de séroconversion) a été définie comme l'augmentation > 4 fois du taux d'anticorps (immunoglobulines) et ceci a été notre outcome primaire. 3. Résultats Soixante transplantés rénaux ont été inclus dans l'étude (thymoglobuline=22, basiliximab=38). Les patients dans le group traité par thymoglobuline étaient plus âgés (p=0.16), avaient des valeurs de créatinine plus élevés (p=0.16) et avaient étés transplanté auparavant (p=0.02). Aucune différence n'a été mise en évidence au niveau de taux des immunoglobulines pour les 3 souches virales entre les 2 groupes (p=0.69 pour H INI, p=0.56 pour H3N2, p=0.7 pour Influenza Β). Le taux de séroconversion à au moins une souche virale a été de 68 % pour le groupe thymoglobuline et de 73% pour le groupe basiliximab (p=0.77). 4. Conclusion Aucune différence significative n'a été démontré dans l'immunogénicité du vaccin de la grippe dans les transplantés rénaux ayant reçu soit du thymoglobuline soit du basiliximab comme traitement d'induction.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in Spain: the MERENA observational cohort study.

To obtain information on cardiovascular morbidity, hypertension control, anemia and mineral metabolism based on the analysis of the baseline characteristics of a large cohort of Spanish patients enrolled in an ongoing prospective, observational, multicenter study of patients with stages 3 and 4 chronic kidney diseases (CKD)

Referral patterns and outcomes in noncritically ill patients with hospital-acquired acute kidney injury.

Background and objectives Despite modern treatment, the case fatality rate of hospital-acquired acute kidney injury (HA-AKI) is still high. We retrospectively described the prevalence and the outcome of HA-AKI without nephrology referral (nrHA-AKI) and late referred HA-AKI patients to nephrologists (lrHA-AKI) compared with early referral patients (erHA-AKI) with respect to renal function recovery, renal replacement therapy (RRT) requirement, and in-hospital mortality of HA-AKI. Design, setting, participants, & measurements Noncritically ill patients admitted to the tertiary care academic center of Lausanne, Switzerland, between 2004 and 2008 in the medical and surgical services were included. Acute kidney injury was defined using the Acute Kidney Injury Network (AKIN) classification. Results During 5 years, 4296 patients (4.12% of admissions) experienced 4727 episodes of HA-AKI during their hospital stay. The mean ± SD age of the patients was 61 ± 15 years with a 55% male predominance. There were 958 patients with nrHA-AKI (22.3%) and 2504 patients with lrHA-AKI (58.3%). RRT was required in 31% of the patients with lrHA-AKI compared with 24% of the patients with erHA-AKI. In the multiple risk factor analysis, compared with erHA-AKI, nrHA-AKI and lrHA-AKI were significantly associated with worse renal outcome and higher in-hospital mortality. Conclusions These data suggest that HA-AKI is frequent and the patients with nrHA-AKI or lrHA-AKI are at increased risk for in-hospital morbidity and mortality.

Alveolar fluid clearance in healthy pigs and influence of positive end-expiratory pressure

INTRODUCTION The objectives were to characterize alveolar fluid clearance (AFC) in pigs with normal lungs and to analyze the effect of immediate application of positive end-expiratory pressure (PEEP). METHODS Animals (n = 25) were mechanically ventilated and divided into four groups: small edema (SE) group, producing pulmonary edema (PE) by intratracheal instillation of 4 ml/kg of saline solution; small edema with PEEP (SE + PEEP) group, same as previous but applying PEEP of 10 cmH2O; large edema (LE) group, producing PE by instillation of 10 ml/kg of saline solution; and large edema with PEEP (LE + PEEP) group, same as LE group but applying PEEP of 10 cmH2O. AFC was estimated from differences in extravascular lung water values obtained by transpulmonary thermodilution method. RESULTS At one hour, AFC was 19.4% in SE group and 18.0% in LE group. In the SE + PEEP group, the AFC rate was higher at one hour than at subsequent time points and higher than in the SE group (45.4% vs. 19.4% at one hour, P < 0.05). The AFC rate was also significantly higher in the LE + PEEP than in the LE group at three hours and four hours. CONCLUSIONS In this pig model, the AFC rate is around 20% at one hour and around 50% at four hours, regardless of the amount of edema, and is increased by the application of PEEP.

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.

BACKGROUND: Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. METHODS: The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. RESULTS: Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. CONCLUSIONS: One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabetes.

Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats

This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r(2)>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

Nephrocalcinosis in a patient with complete distal renal tubular acidosis.

A 35-year-old patient, diagnosed with distal renal tubular acidosis (dRTA), presented with metabolic acidosis (pH =7.1) together with hypokalaemia (2.8 meq/l), hyperlipidaemia and renal insuffi ciency (creatinine clearance = 60.8 ml/min). A 24 h urine examination showed an alkaline pH (7.5), hypercalciuria, hyperkaliuria hypocitraturia (1, 2 ,3). The patient was treated with potassium, citrate supplements and simvastatin . A typical renal colic occurred and an image study revealed considerable bilateral nephrocalcinosis, radio-opaque lithiasis in the left distal lumbar ureter and the right mid lumbar ureter with severe left ureter-hydronephrosis. Ureteroscopy and laser lithotripsy of left lumbar fragments were performed, continuing with the medical treatment (4).