The impact of community-based non-pharmacological interventions on cardiovascular and kidney disease outcomes in remote dwelling Indigenous communities: A scoping review protocol.

INTRODUCTION: Indigenous people represent approximately 5% of the world's population. However, they often have a disproportionately higher burden of cardiovascular disease (CVD) risk and chronic kidney disease (CKD) than their equivalent general population. Several non-pharmacological interventions (e.g., educational) have been used to reduce CVD and kidney disease risk factors in Indigenous groups. The aim of this paper is to describe the protocol for a scoping review that will assess the impact of non-pharmacological interventions carried out in Indigenous and remote dwelling populations to reduce CVD risk factors and CKD. MATERIALS AND METHODS: This scoping review will be guided by the methodological framework for conducting scoping studies developed by Arksey and O'Malley. Both empirical (Medline, Embase, Cochrane Library, CINAHL, ISI Web of Science and PsycINFO) and grey literature references will be assessed if they focused on interventions targeted at reducing CVD or CKD among Indigenous groups. Two reviewers will independently screen references in consecutive stages of title/abstract screening and then full-text screening. Impact of interventions used will be assessed using the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework. A descriptive overview, tabular summaries, and content analysis will be carried out on the extracted data. ETHICS AND DISSEMINATION: This review will collect and analyse evidence on the impact of interventions of research carried out to reduce CVD and CKD among Indigenous populations. Such evidence will be disseminated using traditional approaches that includes open-access peer-reviewed publication, scientific presentations, and a report. Also, we will disseminate our findings to the government and Indigenous leaders. Ethical approval will not be required for this scoping review as the data used will be extracted from already published studies with publicly accessible data.

Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease.

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

NHE8 attenuates Ca2+ influx into NRK cells and the proximal tubule epithelium.

To garner insights into the renal regulation of Ca2+ homeostasis, we performed an mRNA microarray on kidneys from mice treated with the Ca2+-sensing receptor (CaSR) agonist cinacalcet. This revealed decreased gene expression of Na+/H+ exchanger isoform 8 (NHE8) in response to CaSR activation. These results were confirmed by quantitative real-time PCR. Moreover, administration of vitamin D also decreased NHE8 mRNA expression. In contrast, renal NHE8 protein expression from the same samples was increased. To examine the role of NHE8 in transmembrane Ca2+ fluxes, we used the normal rat kidney (NRK) cell line. Cell surface biotinylation and confocal immunofluorescence microscopy demonstrated NHE8 apical expression. Functional experiments found 5-(N-ethyl-N-isopropyl)amiloride (EIPA)-inhibitable NHE activity in NRK cells at concentrations minimally attenuating NHE1 activity in AP-1 cells. To determine how NHE8 might regulate Ca2+ balance, we measured changes in intracellular Ca2+ uptake by live cell Ca2+ imaging with the fluorophore Fura-2 AM. Inhibition of NHE8 with EIPA or by removing extracellular Na+-enhanced Ca2+ influx into NRK cells. Ca2+ influx was mediated by a voltage-dependent Ca2+ channel rather than directly via NHE8. NRK cells express Cav1.3 and display verapamil-sensitive Ca2+ influx and NHE8 inhibition-augmented Ca2+ influx via a voltage-dependent Ca2+ channel. Finally, proximal tubules perused ex vivo demonstrated increased Ca2+ influx in the presence of luminal EIPA at a concentration that would inhibit NHE8. The results of the present study are consistent with NHE8 regulating Ca2+ uptake into the proximal tubule epithelium.

Complete Hypokalemic Quadriparesis as a First Presentation of Sjögren Syndrome.

RATIONALE: We hope to increase awareness that hypokalemic paralysis may be the first presentation of Sjögren syndrome, for which potassium-sparing diuretics can be an effective adjunct to potassium replenishment. PRESENTING CONCERNS: A 73-year-old female presented to a peripheral hospital with quadriparesis and a critically low serum potassium of 1.6 mmol/L with U waves on the electrocardiogram (ECG). The initial arterial blood gas showed a pH of 7.19, bicarbonate of 13 mEq/L, and a CO2 of 35 mm Hg. Over the next 6 days, she was administered a total of 450 mEq of potassium supplements. Despite this, her potassium never increased above 2.9 mmol/L and was thus transferred to the University Hospital for further management. On arrival, her vital signs were within normal limits. Her only other symptoms were fatigue and ocular dryness. Physical exam showed slightly weakened quadriceps muscles bilaterally, graded 4/5. Examination was otherwise unremarkable. Admission investigations included a potassium of 2.8 mmol/L, chloride 118 mmol/L, sodium 136 mmol/L, and eGFR 48 mL/min/1.73 m2. Renin aldosterone ratio was normal. DIAGNOSES: Distal renal tubular acidosis (RTA) was diagnosed based on a normal anion gap metabolic acidosis, positive urine anion gap, and elevated urine potassium to creatinine ratio. Investigation of underlying causes revealed a positive Antinuclear antibody (ANA), elevated rheumatoid factor, and high anti-Ro/SSA titre which directed us toward a unifying diagnosis of Sjögren syndrome. A renal biopsy was undertaken as an outpatient and demonstrated severe interstitial nephritis with acute and chronic components, parenchymal scarring, atrophy, and small vessel arteriosclerosis. INTERVENTIONS: In the acute setting, the patient was treated with bicarbonate and amiloride in addition to potassium supplementation. OUTCOMES: The patient's hypokalemic paralysis and metabolic acidosis were corrected. LESSONS LEARNED: Severe hypokalemic paralysis in distal RTA associated with Sjögren syndrome can be successfully treated with amiloride in addition to potassium supplementation. We also review the literature on the aberrancies seen in H+ATPase, Band 3, Pendrin, and carbonic anhydrase that may underlie the pathogenesis of distal RTA in Sjögren syndrome.

JUSTIFICATION: La paralysie hypokaliémique pourrait être une des premières manifestations du syndrome de Sjögren; syndrome pour lequel les diurétiques épargneurs de potassium pourraient s'avérer un traitement d'appoint pour la régénération du potassium. PRÉSENTATION DU CAS: Nous présentons le cas d'une femme âgée de 73 ans qui s'est présentée dans un hôpital périphérique avec une quadriparésie et un taux de potassium alarmant de 1,6 mmol/L, en plus d'un tracé à l'ECG comportant des ondes U. Les analyses de gazométrie artérielle initiales montraient un pH sanguin à 7,19, un taux de bicarbonate à 13 mEq/L et un taux de CO2 à 35 mm Hg. Malgré l'administration d'un total de 450 mEq de potassium sous forme de suppléments au cours des six jours suivants, le taux de potassium sérique de la patiente n'a jamais dépassé 2,9 mmol/L; on a donc transféré la patiente à l'hôpital universitaire pour un suivi plus poussé. À son arrivée, les signes vitaux se situaient dans les limites normales et les seuls symptômes rapportés étaient de la fatigue et de la sècheresse oculaire. Mis à part une légère faiblesse bilatérale des quadriceps (score de 4/5), l'examen physique n'avait rien d'anormal. Les analyses faites à cette seconde admission ont révélé des taux de 2,8 mmol/L pour le potassium, de 118 mmol/L pour le chlore et de 136 mmol/L pour le sodium. Le DFGe de la patiente se situait à 48 mL/min/1,73 m2 et le rapport rénine/aldostérone était normal. DIAGNOSTIC: Une acidose rénale tubulaire distale (ARTd) a été diagnostiquée par le constat d'une acidose métabolique à trou anionique normale, d'un trou anionique urinaire positif et d'un rapport potassium/créatinine urinaire élevé. La recherche des causes sous-jacentes a révélé une détection d'anticorps antinucléaires ainsi que des valeurs élevées pour le facteur rhumatoïde et le titrage des anti-SSA/Ro, ce qui nous a directement aiguillés vers un diagnostic unificateur du syndrome de Sjögren. Une biopsie rénale pratiquée en consultation externe a révélé la présence d'une néphrite interstitielle grave avec composantes aiguës et chroniques, des lésions au parenchyme, une atrophie et une artériosclérose des artérioles. TRAITEMENT: Aux soins intensifs, la patiente a été traitée avec du bicarbonate et de l'amiloride en plus d'un apport supplémentaire en potassium. RÉSULTATS: La paralysie hypokaliémique et l'acidose métabolique ont été corrigées. CONCLUSION: La paralysie périodique hypokaliémique survenant en contexte d'une ARTd associée au syndrome de Sjögren peut être traitée par l'administration d'amiloride et d'un apport supplémentaire en potassium. Nous dressons également certains constats à la suite d'une revue de la littérature concernant des valeurs aberrantes (notamment dans l'activité de la H+ATPase et de l'anhydrase carbonique, de même que dans les taux de la protéine Band 3 et de la pendrine) qui expliquerait la pathogenèse d'une ARTd dans les cas de syndrome de Sjögren.

Effectiveness of Multifaceted Care Approach on Adverse Clinical Outcomes in Nondiabetic CKD: A Systematic Review and Meta-analysis.

INTRODUCTION: The risk of major adverse events associated with chronic kidney disease (CKD) could potentially be reduced with effective medical interventions. The impact of multifaceted interventions as compared with usual care in patients with nondiabetic CKD is unclear. We performed a systematic review to analyze the impact of multifaceted interventions on reducing the risk of major adverse events in this population. METHODS: Systematic review and meta-analysis. We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library databases for medical literature published up to November 2016. Published original studies and abstracts were reviewed that reported on adult patients in a community or specialty care setting, with 2 or more CKD risk factors, treated with a combination of more than 2 interventions. We included randomized controlled trials, observational studies, and systematic reviews. Studies focused on diabetic patients were excluded. The intervention was defined as a treatment with a combination of 2 or more interventions compared with the usual care. The outcomes were defined as a reduction in the risk of adverse clinical outcomes (renal replacement therapy, all-cause hospitalizations, all-cause and cardiovascular mortality, cardiovascular events) as primary outcomes. Secondary outcomes were optimal risk factor control (attaining guideline concordant blood pressure, reduction of proteinuria, smoking cessation). RESULTS: Five of the 5846 unique citations from our initial literature search met our study criteria. All identified studies reported on patients with CKD and their management. In comparison with usual care, multifaceted interventions tended to reduce all-cause mortality (risk ratio: 0.81, 95% confidence interval: 0.63-1.03) and were associated with a lower risk of progression to kidney failure requiring dialysis (risk ratio: 0.57, 95% confidence interval: 0.35-0.94). Multifaceted interventions were not associated with reducing risk of all-cause hospitalizations (risk ratio: 0.93, 95% confidence interval: 0.71-1.23) or improved blood pressure control (mean difference: -0.48, range: -2.5 to 1.55 mm Hg). DISCUSSION: Multifaceted interventions targeting multiple risk factors tended to reduce the risk of all-cause mortality and reduced the risk to progress to end-stage kidney failure in patients with CKD. There is a need for high-quality studies that can rigorously evaluate a set of interventions targeting multiple domains of CKD management in the population with nondiabetic CKD due to paucity of data in the current published literature.

Cardiac Hepcidin Expression Associates with Injury Independent of Iron.

BACKGROUND: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. METHODS: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. RESULTS: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (ß = 0.734, p < 0.001) and connective tissue growth factor (ß = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. CONCLUSIONS: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

Fluid volume expansion and depletion in hemodialysis patients lack association with clinical parameters.

BACKGROUND: Achievement of normal volume status is crucial in hemodialysis (HD), since both volume expansion and volume contraction have been associated with adverse outcome and events. OBJECTIVES: The objectives of this study are to assess the prevalence of fluid volume expansion and depletion and to identify the best clinical parameter or set of parameters that can predict fluid volume expansion in HD patients. DESIGN: This study is cross-sectional. SETTING: This study was conducted in three hemodialysis units. PATIENTS: In this study, there are 194 HD patients. METHODS: Volume status was assessed by multifrequency bio-impedance spectroscopy (The Body Composition Monitor, Fresenius) prior to the mid-week HD session. RESULTS: Of all patients, 48 % (n = 94) were volume-expanded and 9 % of patients were volume-depleted (n = 17). Interdialytic weight gain was not different between hypovolemic, normovolemic, and hypervolemic patients. Fifty percent of the volume-expanded patients were hypertensive. Paradoxical hypertension was very common (31 % of all patients); its incidence was not different between patient groups. Intradialytic hypotension was relatively common and was more frequent among hypovolemic patients. Multivariate regression analysis identified only four predictors for volume expansion (edema, lower BMI, higher SBP, and smoking). None of these parameters displayed both a good sensitivity and specificity. LIMITATIONS: The volume assessment was performed once. CONCLUSIONS: The study indicates that volume expansion is highly prevalent in HD population and could not be identified using clinical parameters alone. No clinical parameters were identified that could reliably predict volume status. This study shows that bio-impedance can assist to determine volume status. Volume status, in turn, is not related to intradialytic weight gain and is unable to explain the high incidence of paradoxical hypertension.

MISE EN CONTEXTE: L'atteinte d'une volémie normale est primordiale dans le suivi des patients sous hémodialyse. Les états d'expansion et de contraction du volume hydrique sont associés aux complications majeures de l'insuffisance rénale et à une issue défavorable de la maladie. OBJECTIFS DE L'ÉTUDE: Cette étude visait à évaluer la prévalence de l'expansion et de la déplétion des fluides en situation d'hémodialyse. On a également voulu identifier les paramètres cliniques qui pourraient permettre de prévoir les épisodes d'expansion de volume hydrique chez les patients dialysés. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude transversale qui s'est tenue dans trois unités d'hémodialyse, sur un total de 194 patients. METHODES: La volémie des Par spectroscopie de bio-impédance à multifréquence (« Body composition Monitor ¼ de Fresenius) tout juste avant la séance d'hémodialyse prévue en milieu de semaine. RÉSULTATS: De tous les patients qui ont participé à l'étude, une proportion de 48 % (n = 94) était en situation d'expansion volumique alors que 9 % (n = 17) se trouvaient en état de déplétion. Toutefois, la prise de poids interdialytique était semblable pour tous les patients, qu'ils aient été hypovolémiques, normovolémiques ou hypervolémiques avant la séance d'hémodialyse. Il est à noter que la moitié des patients (50 %) en situation d'expansion volémique souffraient également d'hypertension artérielle. De fait, l'hypertension artérielle paradoxale s'est avérée répandue parmi les patients dialysés (31 %), mais aucune variation notable de son incidence n'a été observée dans les différents groupes. Les cas d'hypotension intradialytiques quant à eux, se sont avérés relativement courants, particulièrement chez les sujets hypovolémiques avant la séance d'hémodialyse. L'analyse par régression multivariée n'a révélé que quatre indicateurs susceptibles d'aider à prévoir les épisodes d'expansion de volume : la présence d'œdème, un indice de masse corporelle faible, une pression artérielle systolique élevée avant l'hémodialyse, ainsi que le fait de fumer. Cependant, aucun de ces paramètres n'a présenté une spécificité au plan diagnostique ni une sensibilité particulière pour prévoir les épisodes d'expansion de volume. LIMITES DE L'ÉTUDE: La volémie des participants n'a été mesurée qu'une seule fois lors de cette étude. CONCLUSION: L'étude a révélé une prévalence élevée de l'expansion du volume hydrique chez les patients sous hémodialyse, mais il a été impossible de la détecter à l'aide des paramètres cliniques utilisés. Qui plus est, aucun des paramètres mesurés n'a permis d'anticiper avec certitude des variations de la volémie. Concernant la bio-impédance, les résultats ont révélé qu'elle pourrait aider à évaluer l'expansion de volume chez les patients dialysés. En revanche, cette dernière ne peut être associée directement à la prise de poids intradialytique pas plus qu'elle ne peut à elle seule expliquer la forte incidence d'hypertension artérielle paradoxale.

Neutrophil gelatinase-associated lipocalin (NGAL) in chronic cardiorenal failure is correlated with endogenous erythropoietin levels and decreases in response to low-dose erythropoietin treatment.

BACKGROUND: Neutrophil-gelatinase associated lipocalin (NGAL), a tubular injury marker, is associated with iron metabolism in hemodialysis patients. We investigated whether serum NGAL levels reflect iron metabolism in combined chronic heart failure and chronic kidney disease (CHF/CKD) and whether treatment with low-dose erythropoietin stimulating agent (ESA) modulates NGAL levels. METHODS: In the EPOCARES trial (ClinTrialsNCT00356733) serum NGAL, hepcidin-25, transferrin saturation (TSAT), reticulocyte hemoglobin content (Ret-He) and endogenous erythropoietin (EPO) levels were measured. RESULTS: Baseline serum NGAL levels correlated with cystatin C (r=0.767, p<0.001) and baseline EPO levels (r=-0.395, p=0.003). There was no correlation with baseline TSAT, Ret-He, and hepcidin-25 levels. After two weeks, NGAL levels decreased in the ESA-group (p=0.02), while there was no change in the no-ESA group (p=0.62). The magnitude in NGAL decrease in the ESA-group correlated with baseline EPO levels (r=0.431, p=0.01). CONCLUSIONS: In contrast to in HD patients, in combined CKD/ CHF, serum NGAL levels did not correlate with iron metabolism, hence NGAL might reflect tubular damage in these patients. NGAL levels inversely correlated with baseline EPO levels and decreased in response to short-term ESA treatment, which might reflect an effect of ESA on tubular damage. These findings need to be confirmed and alternative explanations should be evaluated.

Short-term erythropoietin treatment does not substantially modulate monocyte transcriptomes of patients with combined heart and renal failure.

BACKGROUND: Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia. METHODS: Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients. RESULTS: In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable. CONCLUSIONS: In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis. METHODS: The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA). RESULTS: MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without. CONCLUSIONS: ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

Subtotal nephrectomy plus coronary ligation leads to more pronounced damage in both organs than either nephrectomy or coronary ligation.

Coexistence of chronic kidney disease (CKD) and heart failure (HF) in humans is associated with poor outcome. We hypothesized that preexistent CKD worsens cardiac outcome after myocardial infarction, and conversely that ensuing HF worsens progression of CKD. Subtotally nephrectomized (SNX) or sham-operated (CON) rats were subjected to coronary ligation (CL) or sham surgery in week 9 to realize four groups: CON, SNX, CON + CL, and SNX + CL. Blood pressure and renal function were measured in weeks 8, 11, 13, and 15. In week 16, cardiac hemodynamics and end-organ damage were assessed. Blood pressure was significantly lower in SNX + CL vs. SNX. Despite this, glomerulosclerosis was more severe in SNX + CL vs. SNX. Two weeks after CL, SNX + CL had more cardiac dilatation compared with CON + CL (end-diastolic volume index: 0.28 ± 0.04 vs. 0.19 ± 0.03 ml/100 g body wt; mean ± SD, P < 0.001), although infarct size was similar. During follow-up in SNX + CL, ejection fraction declined. Mortality was only observed in SNX + CL (2 out of 9). In SNX + CL, end-diastolic pressure (18 ± 4 mmHg) and tau (29 ± 9 ms), the time constant of active relaxation, were significantly higher compared with SNX (13 ± 3 mmHg, 20 ± 4 ms; P < 0.01) and CON + CL (11 ± 5 mmHg, 17 ± 2 ms; P < 0.01). The diameter of small arterioles in the myocardium was significantly decreased in SNX + CL vs. CON + CL (P < 0.01). Urinary excretion of NO metabolites was significantly lower in SNX + CL compared with both CL and SNX. This study demonstrates the existence of more heart and more kidney damage in a new model of combined CKD and HF than in the individual models. Such enhanced damage appears to be separate from systemic hemodynamic changes. Reduced nitric oxide availability may have played a role in both worsened glomerulosclerosis and cardiac diastolic function and appears to be a connector in the cardiorenal syndrome.

Adverse renal outcomes in subjects undergoing nephrectomy for renal tumors: a population-based analysis.

BACKGROUND: There has been increasing interest in determining renal outcomes after nephrectomy for renal tumors. Previous studies have not assessed all relevant risk factors, including proteinuria. OBJECTIVE: We sought to determine the risk and predictors for the development of adverse renal outcomes in a population-based cohort of subjects undergoing partial or complete nephrectomy. DESIGN, SETTING, AND PARTICIPANTS: A large population-based data set was used to identify all subjects undergoing nephrectomy in Alberta, Canada, from 2002 to 2007 using administrative codes. Comorbid conditions were determined using validated algorithms, and baseline estimated glomerular filtration rate (eGFR) and proteinuria status were determined. MEASUREMENTS: Postsurgical outcomes of end-stage renal disease, acute dialysis, chronic kidney disease (CKD) (eGFR <30 ml/min per 1.73 m(2)), and rapidly progressive CKD (eGFR <60 ml/min per 1.73 m(2) and eGFR loss ≥4 ml/min per 1.73 m(2) per year) were assessed. The risk and risk factors for developing the composite renal outcome were determined using a multivariable Cox proportional hazards model. RESULTS AND LIMITATIONS: Of 1151 subjects, 10.5% developed an adverse renal outcome over a mean of 32 mo. Complete (vs partial) nephrectomy was associated with a hazard ratio (HR) of 1.75 (95% confidence interval [CI], 1.02-2.99) for the primary outcome, as was lower baseline eGFR. Subjects with proteinuria were more likely to experience the primary outcome (42% vs 9%), conferring an adjusted HR of 2.40 (95% CI, 1.47-3.88). CONCLUSIONS: Clinically important adverse renal outcomes are common in patients undergoing nephrectomy for renal tumors. In addition to baseline eGFR and the extent of the renal mass removed, proteinuria is a strong independent risk factor. Assessment of proteinuria, in addition to other risk factors, should be performed to inform prognosis and the optimal treatment strategy.

Short- and long-term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome.

OBJECTIVE: Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients. DESIGN: Open-label randomized trial. SETTING: Part of the EPOCARES-trial, conducted in Utrecht (Netherlands). PATIENTS: Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy. MAIN OUTCOME MEASURES: CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks. RESULTS: Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels. CONCLUSIONS: CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Residual renal function after partial or radical nephrectomy for renal cell carcinoma.

Renal cell carcinoma (RCC) is often detected incidentally and early. Currently, open partial nephrectomy and laparoscopic total nephrectomy form competing technologies. The former is invasive, but nephron-sparing; the other is considered less invasive but with more loss of renal mass. Traditionally, emphasis has been placed on oncologic outcomes. However, a patient with an excellent oncologic outcome may suffer from morbidity and mortality related to renal failure. Animal models with hypertension and diabetic renal disease indicate accelerated progression of pre-existing disease after nephrectomy. Patients with RCC are older and they have a high prevalence of diabetes and hypertension. The progression of renal failure may also be accelerated after a nephrectomy. Our analysis of the available literature indicates that renal outcomes in RCC patients after surgery are relatively poorly defined. A strategy to systematically evaluate the renal function of patients with RCC, with joint discussion between the nephrologist and the oncologic team, is strongly advocated.

IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells.

IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-gamma (IFNgamma)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNgamma activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNgamma pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNgamma-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNgamma also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNgamma, 2) IFNgamma-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNgamma, and 3) a set of target genes that were increased upon IL-6 or IFNgamma alone, or combined IFNgamma and IL-6. In summary, by increasing SOCS3 expression in EC, IFNgamma can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNgamma-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction.

Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study.

BACKGROUND: Anemia is common in patients with the combination of chronic heart failure and chronic kidney disease and is associated with increased mortality. Recent clinical studies suggest that recombinant human erythropoietin (EPO) treatment has desirable as well as undesirable effects, related to its hematopoietic or nonhematopoietic effects. Therefore a translational study is needed to elucidate mechanistic aspects of EPO treatment. METHODS: In this open-label randomized 12-month trial (the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome [EPOCARES]), patients with the combination of chronic heart failure and chronic kidney disease (glomerular filtration rate 20-70 ml/min) and mild anemia (hemoglobin 10.3-12.6 g/dL in men, and 10.3-11.9 g/dL in women) are being randomized into 3 groups: 1 group (n=25) receives a fixed dose of 50 IU/kg per week EPO to increase hemoglobin level to a maximum of 13.7 g/dL for men and 13.4 g/dL for women; another group (n=25) is treated with 50 IU/kg per week EPO maintaining baseline hemoglobin levels for the first 6 months by phlebotomy. The control group (n=25) receives standard care without EPO. RESULTS: Cardiac and renal function as well as a panel of biomarkers and iron parameters are being assessed. Furthermore, the effects of EPO on monocyte gene expression profiles and on endothelial progenitor cells are being evaluated. CONCLUSION: This translational study is designed primarily to discern hematopoietic from nonhematopoietic effects of EPO in cardiorenal patients. The study will add insights into the mechanisms that could explain the fragile balance between desirable and undesirable effects of EPO (Trial registration: ClinicalTrials.gov identifier NCT00356733).

Progenitor cells and vascular function are impaired in patients with chronic kidney disease.

BACKGROUND: Endothelial dysfunction contributes to accelerated atherosclerosis in chronic kidney disease (CKD). Bone marrow-derived endothelial progenitor cells (EPC) constitute an endogenous vascular repair system protecting against atherosclerosis. Smooth muscle progenitor cells (SPC) may stimulate atherosclerosis development. We hypothesized that an imbalance in EPC and SPC occurs in CKD, which may contribute to the increased cardiovascular disease (CVD) risk. METHODS: EPC and SPC outgrowth from mononuclear cells (MNC), EPC migratory function and circulating CD34(+)KDR(+)-EPC were measured in 49 patients with varying degrees of CKD on regular therapy and 33 healthy volunteers. Renal function, CKD cause, CVD history and endothelial dysfunction parameters were determined as factors of influence on progenitor cells. RESULTS: Patients had reduced EPC outgrowth compared to controls [9 (2-22) vs 12 (1-38) cells/10(3) MNC, P = 0.026], independent of CKD cause and degree, whereas SPC outgrowth levels were higher in patients with more impaired kidney function (r = -0.397, P = 0.008). Patients had lower CD34(+)KDR(+)-EPC compared to controls [9 (0-52) vs 19 (4-110) cells/10(5) granulocytes, P = 0.004]. CVD history and increased endothelial dysfunction markers were related to lower EPC levels. Progenitor cell outgrowth was shifted towards SPC with progression of endothelial damage. Reduction in EPC could not be attributed to decreases in progenitor cell-mobilizing factors SDF-1 alpha and VEGF as levels increased with progressive kidney and endothelial dysfunction, while EPC remained low. CONCLUSIONS: Our data suggest that, already in mild CKD, EPC-mediated endogenous vascular regeneration is impaired, while SPC levels increase with declining kidney function.

Increased SOCS expression in peripheral blood mononuclear cells of end stage renal disease patients is related to inflammation and dialysis modality.

Inflammation is a characteristic of cardiovascular disease and is increased in end-stage renal disease. Suppressors of cytokine signaling (SOCS) inhibit and reflect activation of intracellular inflammatory pathways. We hypothesized that SOCS expression in peripheral blood mononuclear cells of end stage renal disease patients is increased. Whether SOCS expression in peripheral blood mononuclear cells is related to inflammation, dialysis, and dialysis modality was investigated. Monocytes and lymphocytes were isolated from peripheral blood mononuclear cells of patients not on dialysis (n=8), on peritoneal dialysis (n=8), on hemodialysis (n=14) and of healthy control (n=15) subjects. SOCS expression was assessed by real-time quantitative PCR and plasma cytokines by ELISA. In end stage renal disease patients monocyte SOCS1, and lymphocyte SOCS1 and cytokine-inducible SH2 containing protein-1 (CIS-1) gene expression were increased along with increased plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)alpha ,and C-reactive protein (CRP). Monocyte SOCS1 correlated with IL-6. Lymphocyte CIS-1 was increased in non-dialysis and peritoneal dialysis but not in hemodialysis patients. Lymphocyte CIS-1 in peritoneal dialysis patients correlated with plasma TNFalpha. Despite the relatively low number of patients studied we observed increased expression of SOCS1 in both monocytes and lymphocytes, and of CIS-1 solely in lymphocytes of the patients. SOCS expression was related to increased systemic inflammation, illustrated by a significant correlation between monocyte SOCS1 and plasma IL-6. SOCS expression in peripheral blood mononuclear cells was also affected by hemodialysis, indicated by increased lymphocyte CIS-1 in non-dialysis and peritoneal dialysis but not in hemodialysis patients. We suggest that increased SOCS expression in peripheral blood mononuclear cells of end stage renal disease patients reflects whether and to which extent systemic inflammation activates the intracellular inflammatory pathways.

Increased expression of SOCS3 in monocytes and SOCS1 in lymphocytes correlates with progressive loss of renal function and cardiovascular risk factors in chronic kidney disease.

Inflammation, an independent cardiovascular disease risk factor is common in patients with chronic kidney disease. Suppressors of cytokine signaling (SOCS) are induced by cytokines in a variety of cells and modulate inflammatory responses. We hypothesized that in chronic kidney disease, SOCS expression in peripheral blood mononuclear cells is increased, and related to inflammation and renal function. We also tested correlations between SOCS expression and biomarkers and risk factors of cardiovascular disease. Whether monocytes and lymphocytes differentially respond to interleukin-6 (IL-6) was tested ex vivo. Monocytes and lymphocytes were isolated from peripheral blood of chronic kidney disease patients (n=9) and controls (n=11). In three other healthy subjects, whole blood was incubated with IL-6 before cell isolation. SOCS expression was assessed by real-time quantitative PCR. Plasma cytokines were measured as well as pulse wave velocity. SOCS3 expression was increased in monocytes and SOCS1 in lymphocytes along with increased plasma levels of IL-6 and tumor necrosis factor-alpha (TNFalpha) in chronic kidney disease patients. While monocyte SOCS3 correlated with glomerular filtration rate, urea and diastolic blood pressure, lymphocyte SOCS1 correlated with TNFalpha, pulse wave velocity and systolic blood pressure. IL-6 stimulation of whole blood caused expression of different SOCS genes in monocytes and lymphocytes. Increased expression of SOCS3 in monocytes versus SOCS1 in lymphocytes coincided with elevated plasma levels of IL-6 and TNFalpha, suggesting that these cell types process the uremic milieu differently. This could reflect cell-specific responses to inflammation, as supported by our ex vivo study. Moreover, increased SOCS expression in peripheral blood mononuclear cells correlated with decreased renal function. Since chronic kidney disease predisposes to cardiovascular disease, we speculate that increased SOCS expression in peripheral blood mononuclear cells could be a new marker of cardiovascular disease in chronic kidney disease patients.

Technology insight: Innovative options for end-stage renal disease--from kidney refurbishment to artificial kidney.

The steadily growing number of patients with chronic kidney disease who will eventually develop end-stage renal disease, together with the qualitative limitations of currently available renal replacement therapies, have triggered the exploration of innovative strategies for renal replacement therapy and for salvage of renal function. Currently, new hemodialysis modalities and membranes are being used with the aim of increasing clearance of uremic toxins to afford better metabolic control. In addition to these conventional approaches, there are four innovative potential solutions to the problem of replacing renal function when kidneys fail. The first is a small, implantable device with the potential to be supplemented with human cells ('artificial kidney'). The second involves restoration of the damaged kidney by harnessing recent advances in stem-cell technology and knowledge of developmental programing ('refurbished kidney'). The third is (partially) growing a kidney in vitro with the use of therapeutic cloning ('cultured kidney'). The fourth innovative solution involves the use of other organs to replace various renal functions ('distributed kidney'). In this article we review the efforts that have been made to improve renal replacement therapies, and explore innovative approaches. We will not cover all potential solutions in detail. Rather, we aim to indicate directions of future endeavor and arouse enthusiasm in clinicians and scientists for exploration of these exciting avenues.