Risk-Based Triage for Nephrology Referrals Using the Kidney Failure Risk Equation.

BACKGROUND: In some jurisdictions, routine reporting of the estimated glomerular filtration rate (eGFR) has led to an increase in nephrology referrals and wait times. OBJECTIVE: We describe the use of the Kidney Failure Risk Equation (KFRE) as part of a triage process for new nephrology referrals for patients with chronic kidney disease stages 3 to 5 in a Canadian province. DESIGN: A quasi-experimental study design was used. SETTING: This study took place in Manitoba, Canada. MEASUREMENTS: Demographics, laboratory values, referral numbers, and wait times were compared between periods. METHODS: In 2012, we adopted a risk-based cutoff of 3% over 5 years using the KFRE as a threshold for triage of new referrals. Referrals who did not meet other prespecified criteria (such as pregnancy, suspected glomerulonephritis, etc) and had a kidney failure risk of <3% over 5 years were returned to primary care with recommendations based on diabetes and hypertension guidelines. The average wait time and number of consults seen between the pretriage (January 1, 2011, to December 31, 2011) and posttriage period (January 1, 2013, to December 31, 2013) were compared using a general linear model. RESULTS: In the pretriage period, the median number of referrals was 68/month (range: 44-76); this increased to 94/month (range: 61-147) in the posttriage period. In the posttriage period, 35% of referrals were booked as urgent, 31% as nonurgent, and 34% of referrals were not booked. The median wait times improved from 230 days (range: 126-355) in the pretriage period to 58 days (range: 48-69) in the posttriage period. LIMITATIONS: We do not have long-term follow-up on patients triaged as low risk. Our study may not be applicable to nephrology teams operating under capacity without wait lists. We did not collect detailed information on all referrals in the pretriage period, so any differences in our pretriage and posttriage patient groups may be unaccounted for. CONCLUSIONS: Our risk-based triage scheme is an effective health policy tool that led to improved wait times and access to care for patients at highest risk of progression to kidney failure.

CONTEXTE: Dans certaines régions administratives, la déclaration systématique des valeurs de débit de filtration glomérulaire estimé (DFGe) a conduit à une augmentation des recommandations de patients pour un suivi en néphrologie et, par conséquent, du temps d'attente pour obtenir une consultation. OBJECTIF DE L'ÉTUDE: Dans cette étude, nous décrivons l'utilisation de l'équation de risque pour l'insuffisance rénale terminale (KFRE) dans le cadre du processus de triage des nouvelles recommandations pour un suivi en néphrologie de patients atteints d'insuffisance rénale chronique de stade 3 à stade 5 dans une province canadienne. TYPE D'ÉTUDE: On a utilisé un modèle quasi expérimental pour cette étude. CADRE DE L'ÉTUDE: Cette étude a eu lieu dans la province du Manitoba au Canada. MESURES: Nous avons comparé les données démographiques et les valeurs de laboratoire des patients, de même que le nombre de nouvelles recommandations de patients en néphrologie et le temps d'attente pour obtenir une consultation entre les périodes choisies. MÉTHODOLOGIE: En 2012, à l'aide de la KFRE, nous avons établi un risque de défaillance rénale de 3 % sur 5 ans comme valeur seuil pour le triage des nouvelles recommandations de patients pour un suivi en néphrologie. Les patients redirigés qui ne respectaient pas les autres critères de triage spécifiés au préalable, notamment la grossesse ou une glomérulonéphrite soupçonnée, de même que ceux qui présentaient un risque de défaillance rénale inférieur à 3 % sur 5 ans ont été retournés vers les soins primaires avec une recommandation fondée sur les directives du diabète et de l'hypertension. Le délai d'attente moyen et le nombre de consultations observés entre la période prétriage (du 1er janvier 2011 au 31 décembre 2011) et la période suivant le triage (du 1er janvier 2013 au 31 décembre 2013) ont été comparés à l'aide d'un modèle linéaire général. RÉSULTATS: Au cours de la période de prétriage, le nombre médian de recommandations en néphrologie a été de 68 par mois (intervalle : 44 à 76 par mois). Ce nombre est passé à 94 par mois (intervalle : 61 à 147 par mois) dans la période suivant le triage. Au cours de cette période, 35 % des recommandations étaient identifiées comme étant urgentes, 31 % comme étant non urgents et 34 % ne portaient aucune mention. Le temps d'attente médian s'est amélioré, passant de 230 jours (intervalle : 126 à 355 jours) en période de prétriage à 58 jours (intervalle : 48 à 69 jours) dans la période post-triage. LIMITES DE L'ÉTUDE: Nous n'avons aucun suivi à long terme pour les patients classés à faible risque de défaillance rénale sur 5 ans. De plus, il est possible que notre étude ne puisse s'appliquer aux équipes de néphrologues qui opèrent en dessous de leur capacité et donc, sans liste d'attente. Enfin, nous ne pouvons tenir compte des différences susceptibles d'être observées entre les groupes de patients vus en prétriage et en post-triage puisque nous n'avons pas recueilli de renseignements détaillés sur tous les patients recommandés. CONCLUSIONS: Notre système de triage axé sur les risques de défaillance rénale sur 5 ans est un outil efficace d'élaboration de politiques en santé. Ce système conduit à l'amélioration du temps d'attente et à un accès plus facile aux soins pour les patients à haut risque de voir leur état progresser vers l'insuffisance rénale.

Risk Prediction in CKD: The Rational Alignment of Health Care Resources in CKD 4/5 Care.

CKD is a well-recognized global epidemic with consequences on patient morbidity, mortality, and health care resources. In the United States and Canada, a financial premium is often paid to programs and providers for caring for patients with Stage 4 to 5 CKD (not on dialysis) and is justified by the intensive care required by these patients, particularly in preparation for dialysis. About half of all patients with CKD Stages 3 and 4 never progress to kidney failure, and more than a quarter of them have stable kidney function for years. Among patients with Stage 3 CKD, even fewer progresses to kidney failure but small subpopulations with certain characteristics (eg, younger age, higher levels of proteinuria) have a more predictable trajectory. Clearly, a more robust method of screening patients for nephrology referral and subsequent enrollment into multidisciplinary clinics is needed to provide better efficiency within the health care system. The Kidney Failure Risk Equation is a generalizable CKD risk prediction model that has been externally validated and allows for the efficient risk-based triaging of nephrology referrals with a significant benefit to decreasing wait times. It is also efficiently used in a multidisciplinary kidney disease clinic with aiding timing in modality planning and frequency of follow-ups. The overall potential benefit of this system should allow for appropriate allocation of human resources to those at highest risk to yield optimal care in the most cost-effective manner to the health care system.

Resveratrol and small artery compliance and remodeling in the spontaneously hypertensive rat.

BACKGROUND: Small arteries from the spontaneously hypertensive rat (SHR) exhibit abnormal stiffness and geometry. This study investigated the effects of resveratrol, a polyphenol found in foods such as red grapes, on small arteries in SHR. METHODS: Wistar-Kyoto (WKY) rats and SHR were treated with resveratrol (2.5 mg/kg/day) for 10 weeks. Mesenteric small artery segments (third-order branches) were mounted in a pressure myograph, and vascular geometry and mechanical properties were calculated from lumen and media dimensions measured at incremental intraluminal pressures. Systolic blood pressure was measured by tail-cuff plethysmography. RESULTS: Increased compliance and reduced wall component stiffness were observed in SHR arteries vs. WKY arteries. Though resveratrol did not prevent lowering of wall component stiffness, it did attenuate, at least in part, the increased compliance of SHR arteries. In contrast, resveratrol increased compliance and reduced wall component stiffness in WKY arteries. SHR arteries exhibited remodeling that consisted of narrowed lumens, thickened media widths, and augmented media-to-lumen ratios. Resveratrol partially attenuated the remodeling process and also abolished exaggerated ERK signaling and expression of proliferating cell nuclear antigen (a marker of proliferation) in SHR arteries. The latter effects might be related to the ability of resveratrol to alleviate oxidative stress in SHR and enhance protein kinase G (PKG) activity. Elevated blood pressure in 20-week-old SHR was unaffected by resveratrol. CONCLUSIONS: The ability of resveratrol to limit the increase in compliance of SHR arteries is likely related to inhibitory effects on remodeling and pro-growth ERK signaling rather than blood pressure or arterial wall component stiffness.

Defects in ryanodine receptor function are associated with systolic dysfunction in rats subjected to volume overload.

Cardiac hypertrophy is the compensatory enlargement of the heart aimed at reducing stress induced by either pressure overload or volume overload (VO); however, sustained hypertrophy leads to cardiac dysfunction. We hypothesize that cardiac dysfunction which develops due to VO will be associated with abnormalities in sarcoplasmic reticulum (SR) function. Volume overload was induced in rats by aortocaval shunt surgery ('VO rats'). Echocardiographic measurements were used to compare cardiac structure and function in control and VO rats. The SR was isolated from left ventricular tissue. Sarcoplasmic reticulum Ca(2+) uptake and SR Ca(2+) release were examined by the filtration method. The expression levels of SR proteins were assessed by Western immunoblotting. Rats subjected to VO developed eccentric hypertrophy. Diastolic function in VO rats was improved at all time points and was associated with elevated SR Ca(2+) uptake at 16 and 28 weeks. Sarcoendoplasmic reticulum ATPase 2a protein level was increased at 16 weeks but normalized at 28 weeks; Amounts of phospholamban protein were unaltered, but Serine16 phospholamban and Threonine17 phospholamban were reduced at 28 weeks. Systolic function was impaired in the VO rats at 16 and 28 weeks and was associated with reduced Ca(2+) release at the 28 week time point. The ryanodine receptor 2 (RyR2) protein level was reduced at 28 weeks; RyR2 phosphorylation status and the amount of FK-binding protein 12.6 were increased at 28 weeks. On the basis of the results, we conclude that the progression of hypertrophy due to VO in rats is accompanied by the impairment of systolic function, which in turn is associated with defects in RyR2 expression and function.

Resveratrol arrests and regresses the development of pressure overload- but not volume overload-induced cardiac hypertrophy in rats.

Cardiac hypertrophy is a compensatory enlargement of the heart due to either volume overload (VO) and/or pressure overload (PO) that develops into heart failure if left untreated. The polyphenol resveratrol has been reported to regress PO-induced cardiac hypertrophy in rats. Our aim in this study was to assess the effectiveness of resveratrol on VO-induced cardiac hypertrophy. Sprague Dawley rats were subjected to aortocaval shunt and abdominal aortic banding surgeries to create VO and PO, respectively; sham-operated rats served as controls. To arrest the development of cardiac hypertrophy, daily resveratrol treatment (2.5 mg/kg body weight) was started 2 d postsurgery for 26 d and assessed by echocardiography at 2, 14, and 28 d postsurgery. Similarly, to regress cardiac hypertrophy resveratrol treatment was started after structural and functional abnormalities developed (14 d postsurgery) for 14 d and assessed by echocardiography at 14 and 28 d postsurgery. VO surgeries induced eccentric hypertrophy characterized by increased left ventricle internal dimensions (LVID) without wall thickening. Conversely, PO induced concentric hypertrophy with increased wall thickness without change in LVID. Lipid peroxidation, a marker for oxidative stress, was significantly elevated in both PO and VO rats. Resveratrol treatment arrested the development and regressed abnormalities in cardiac structure and function in PO but not VO rats. Treatment with resveratrol also significantly reduced oxidative stress in cardiac tissue of PO and VO rats. The results on cardiac structure and function demonstrate a potential for resveratrol in the treatment of cardiac hypertrophy due to PO but not VO.

Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure.

BACKGROUND: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. METHODS: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with resveratrol (2.5 mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. RESULTS: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. CONCLUSIONS: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

A consensus rating method for small virus-retentive filters. I. Method development.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. One goal of the task force was to develop a test method for small virus-retentive filters. Because small virus-retentive filters present unique technical challenges, the test method development process was guided by laboratory studies to determine critical variables such as choice of bacteriophage challenge, choice of model protein, filtration operating parameters, target log10 reduction value, and filtration endpoint definition. Based on filtration, DLS, electrospray differential mobility analysis, and polymerase chain reaction studies, a final rating based on retention of bacteriophage PP7 was chosen by the PDA Virus Filter Task Force. The detailed final consensus filter method was published in the 2008 update of PDA Technical Report 41. Virus Filtration.

A consensus rating method for small virus-retentive filters. II. Method evaluation.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. A test method based on bacteriophage PP7 retention was chosen based on developmental studies. The detailed final consensus filter method is published in the 2008 update of PDA Technical Report 41: Virus Filtration. Here, we evaluate the method and find it to be acceptable for testing scaled-down models of small virus-retentive filters from four manufacturers. Three consecutive lots of five filter types were tested (Pegasus SV4, Viresolve NFP, Planova 20N and 15N, Virosart CPV). Each passed the criteria specified in the test method (i.e., >4 log10 PP7 retention, >90% intravenous immunoglobulin passage, and passing integrity/installation testing) and was classified as PP7-LRV4.

Prevention of concentric hypertrophy and diastolic impairment in aortic-banded rats treated with resveratrol.

This study was designed to examine the effects of the antioxidant resveratrol on cardiac structure and function in pressure overload (PO)-induced cardiac hypertrophy. Male Sprague-Dawley rats were subjected to sham operation and the aortic banding procedure. A subgroup of sham control and aortic-banded rats were treated with resveratrol for 2 wk after surgery. Echocardiographic analysis of cardiac structure and function along with Western blot analysis of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and redox factor-1 (ref-1) were performed in all groups after 4 wk of surgery. Banded rats showed significantly increased left ventricle-to-body weight ratio. Echocardiographic analysis showed that the interventricular septal wall thickness and left ventricular posterior wall thickness at systole and diastole were significantly increased in banded rats. Also, a significant increase in isovolumic relaxation time was observed in banded rats. Measured eNOS, iNOS, and ref-1 protein levels were significantly reduced in banded rats. Resveratrol treatment prevented the above changes in cardiac structure, function, and protein expression in banded rats. Aortic banding after 4 wk resulted in concentric remodeling and impaired contractile function due to PO on the heart. The 2-wk treatment with resveratrol was found to abolish PO-induced cardiac hypertrophy. Resveratrol may therefore be beneficial against PO-induced cardiac hypertrophy found in clinical settings of hypertension and aortic valve stenosis.

Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels.

Many commonly used medications can cause long QT syndrome and thus increase the risk of life-threatening arrhythmias. High-affinity human Ether-à-go-go-related gene (HERG) potassium channel blockade by structurally diverse compounds is almost exclusively responsible for this side effect. Understanding drug-HERG channel interactions is an important step in avoiding drug-induced long QT syndromes. Previous studies have found that disrupting HERG inactivation reduces the degree of drug block and have suggested that the inactivated state is the preferential state for drug binding to HERG channels. However, recent studies have also shown that inactivation does not dictate drug sensitivity of HERG channels. In the present study, we examined the effect of inactivation gating on cisapride block of HERG. Modulation of HERG inactivation was achieved by either changing extracellular K+ or Cs+ concentrations or by mutations of the channel. We found that although inactivation facilitated cisapride block of the HERG K+ current, it was not coupled with cisapride block of HERG when the Cs+ current was recorded. Furthermore, cisapride block of the HERG K+ current was not linked with inactivation in the mutant HERG channels F656V and F656M. Our results suggest that inactivation facilitates cisapride block of HERG channels through affecting the positioning of Phe-656.