DEVELOPING THERAPIES FOR C3G: REPORT OF THE KIDNEY HEALTH INITIATIVE C3G TRIAL ENDPOINTS WORK GROUP.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work group reviewed the available evidence and uncertainties for the association between the three prespecified endpoints -- (1) proteinuria; (2) estimated glomerular filtration rate (eGFR); and (3) histopathology -- and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed endpoints they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, the evidence, and uncertainties, supporting the endpoints. Given the limitations of the available data, the workgroup was unable to define a minimum threshold for change in any of the endpoints that might be considered clinically meaningful. The workgroup concluded that a favorable treatment effect on all three endpoints would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the endpoints in the aforementioned trials.

Improving Clinical Care for Children With CKD: A Report From a National Kidney Foundation Scientific Workshop.

Development of clinical guidelines and recommendations to address the care of pediatric patients with chronic kidney disease (CKD) has rarely included the perspectives of providers from a variety of health care disciplines or the patients and parents themselves. Accordingly, the National Kidney Foundation hosted an in-person, one and a half-day workshop that convened a multidisciplinary group of physicians, allied health care professionals, and pediatric patients with CKD and their parents, with the goal of developing key clinical recommendations regarding best practices for the clinical management of pediatric patients living with CKD. The key clinical recommendations pertained to 5 broad topics: addressing the needs of patients and parents/caregivers; modifying the progression of CKD; clinical management of CKD-mineral and bone disorder and growth retardation; clinical management of anemia, cardiovascular disease, and hypertension; and transition and transfer of pediatric patients to adult nephrology care. This report describes the recommendations generated by the participants who attended the workshop.

Risk Reduction Strategy to Decrease Incidence of Retained Surgical Items.

BACKGROUND: Retained surgical items (RSIs) are rare but serious events associated with significant morbidity and costs. We assessed the effectiveness of radiofrequency (RF) detection technology and Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) in reducing the incidence of RSIs. STUDY DESIGN: All RSIs reported to the New York Patient Occurrence Reporting and Tracking System at five large urban teaching hospitals from 2007 to 2017 were analyzed. In 2012, TeamSTEPPS training was provided to all perioperative staff at each site, and use of RF detection became required in all procedures. The incidence of events before and after the interventions were compared using odds ratios. RESULTS: A total of 997,237 operative procedures were analyzed. After the interventions, the incidence of RSIs decreased from 11.66 to 5.80 events per 100,000 operations (odds ratio [OR] [95% CI] = 0.50 [0.32 to 0.78]). The frequency of RSIs involving RF-detectable items decreased from 5.21 to 1.35 events per 100,000 operations (OR [95% CI] = 0.26 [0.11 to 0.60]). The difference in RSIs involving non-RF-detectable surgical items was not statistically significant. CONCLUSIONS: The incidence of RSIs was significantly lower during the time period after implementing RF detection technology and after TeamSTEPPS training, primarily driven by a decrease in retained RF-detectable items. RF detection technology may be worth pursuing for hospitals looking to decrease RSI frequency. The benefit of TeamSTEPPS training alone may not result in a reduction of RSIs.

Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

Clinical trial recommendations for potential Alport syndrome therapies.

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and-most critically-patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

Provider preferences for postoperative analgesia in obese and non-obese patients undergoing ambulatory surgery.

BACKGROUND: Few guidelines exist on safe prescription of postoperative analgesia to obese patients undergoing ambulatory surgery. This study examines the preferences of providers in the standard treatment of postoperative pain in the ambulatory setting. METHODS: Providers from five academic medical centers within a single US city were surveyed from May-September 2015. They were asked to provide their preferred postoperative analgesic routine based upon the predicted severity of pain for obese and non-obese patients. McNemar's tests for paired observations were performed to compare prescribing preferences for obese vs. non-obese patients. Fisher's exact tests were performed to compare preferences based on experience: > 15 years vs. ≤15 years in practice, and attending vs. resident physicians. RESULTS: A total of 452 providers responded out of a possible 695. For mild pain, 119 (26.4%) respondents prefer an opioid for obese patients vs. 140 (31.1%) for non-obese (p = 0.002); for moderate pain, 329 (72.7%) for obese patients vs. 348 (77.0%) for non-obese (p = 0.011); for severe pain, 398 (88.1%) for obese patients vs. 423 (93.6%) for non-obese (p < 0.001). Less experienced physicians are more likely to prefer an opioid for obese patients with moderate pain: 70 (62.0%) attending physicians with > 15 years in practice vs. 86 (74.5%) with ≤15 years (p = 0.047), and 177 (68.0%) attending physicians vs. 129 (83.0%) residents (p = 0.002). CONCLUSIONS: While there is a trend to prescribe less opioid analgesics to obese patients undergoing ambulatory surgery, these medications may still be over-prescribed. Less experienced physicians reported prescribing opioids to obese patients more frequently than more experienced physicians.

Is video observation as effective as live observation in improving teamwork in the operating room?

BACKGROUND: Teamwork in the operating room decreases the risk of preventable patient harm. Observation in the operating room allows for evaluation of compliance with best-practice surgical guidelines. This study examines the relative ability of video and live observation to promote operating room teamwork. METHODS: Video and audio cameras were installed in 2014 into all operating rooms at an 875-bed, urban teaching hospital. Recordings were chosen at random for review by an internal quality improvement team. Concurrently, live observers were deployed into a random selection of operations. A customized tool was used to evaluate compliance to TeamSTEPPS skills during surgical briefs and debriefs. RESULTS: A total of 1,410 briefs were evaluated: 325 (23%) through live observation and 1,085 (77%) through video; 1,398 debriefs were evaluated: 166 (12%) live and 1,232 (88%) video. For briefs, greater compliance was observed under live observation compared to video for recognition of team membership (87% vs 44%, P<.001), anticipation of complex procedural events (61% vs 45%, P<.001), and monitoring of resources (58% vs 42%, P<.001). For debriefs, greater compliance was observed under live observation for determination of team structure (90% vs 60%, P<.001), establishment of a leader (70% vs 51%, P<.001), postoperative planning (77% vs 48%, P<.001), case review and feedback (49% vs 33%, P<.001), team engagement (64% vs 41%, P<.001), and check back (61% vs 46%, P<.001) compared to video. CONCLUSION: Video observations may not be as effective as evaluating live performance in promoting teamwork in the OR. Live observation enables immediate feedback, which may improve behavior and decrease barriers to compliance with surgical safety practices.

The value proposition of simulation-based education.

Simulation has become an integral part of physician education, and abundant evidence confirms that simulation-based education improves learners' skills and behaviors and is associated with improved patient outcomes. The resources required to implement simulation-based education, however, have led some stakeholders to question the overall value proposition of simulation-based education. This paper summarizes the information from a special panel on this topic and defines research priorities for the field. Future work should focus on both outcomes and costs, with robust measurement of resource investments, provider performance (in both simulation and real settings), patient outcomes, and impact on the health care organization. Increased attention to training practicing clinicians and health care teams is also essential. Clarifying the value proposition of simulation-based education will require a major national effort with funding from multiple sponsors and active engagement of a variety of stakeholders.

A perioperative care map improves outcomes in patients with morbid obesity undergoing major surgery.

BACKGROUND: The surgical management of patients with morbid obesity (body mass index ≥ 40) is notable for a relatively high risk of complications. To address this problem, a perioperative care map was developed using precautions and best practices commonly employed in bariatric surgery. It requires additional medical assessments, sleep apnea surveillance, more stringent guidelines for anesthetic management, and readily available bariatric operating room equipment, among other items. This care map was implemented in 2013 at 4 major urban teaching hospitals for use in patients undergoing all types of nonambulatory surgery with a body mass index greater than 40 kg/m2. The impact on patient outcomes was evaluated. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to compare 30-day outcomes of morbidly obese patients before the year 2013 and after the years 2015 care-map implementation. In addition, trends in 30-day outcomes for morbidly obese patients were compared with those for non-obese patients. RESULTS: Morbidly obese patients, between 2013 and 2015, saw an adjusted decrease in the rate of unplanned return to the operating room (OR = 0.49; P = .039), unplanned readmission (OR = 0.57; P = .006), total duration of stay (-0.87 days; P = .009), and postoperative duration of stay (-0.69 days; P = .007). Of these, total duration of stay (-0.86 days; P = .015), and postoperative duration of stay (-0.69 days; P = .012) improved significantly more for morbidly obese patients than for nonmorbidly obese patients. CONCLUSION: Outcomes in morbidly obese patients improved from 2013 to 2015. Implementation of a perioperative care map may have contributed to these improvements. The care map should be further investigated and considered for more widespread use.

Perioperative care map improves compliance with best practices for the morbidly obese.

BACKGROUND: Morbid obesity can complicate perioperative management. Best practice guidelines have been published but are typically followed only in bariatric patients. Little is known regarding physician awareness of and compliance with these clinical recommendations for nonbariatric operations. Our study evaluated if an educational intervention could improve physician recognition of and compliance with established best practices for all morbidly obese operatively treated patients. METHODS: A care map outlining best practices for morbidly obese patients was distributed to all surgeons and anesthesiologists at 4 teaching hospitals in 2013. Pre- and postintervention surveys were sent to participants in 2012 and in 2015 to evaluate changes in clinical practice. A chart audit performed postintervention determined physician compliance with distributed guidelines. RESULTS: In the study, 567 physicians completed the survey in 2012 and 375 physicians completed the survey in 2015. Postintervention, statistically significant improvements were seen in the percentage of surgeons and anesthesiologists combined who reported changing their management of morbidly obese, operatively treated patients to comply with best practices preoperatively (89% vs 59%), intraoperatively (71% vs 54%), postoperatively (80% vs 57%), and overall (88% vs 72%). Results were similar when surgeons and anesthesiologists were analyzed separately. A chart audit of 170 cases from the 4 hospitals found that 167 (98%) cases were compliant with best practices. CONCLUSION: After care map distribution, the percentage of physicians who reported changing their management to match best practices significantly improved. These findings highlight the beneficial impact this educational intervention can have on physician behavior. Continued investigation is needed to evaluate the influence of this intervention on clinical outcomes.

Angiotensinogen Exerts Effects Independent of Angiotensin II.

OBJECTIVE: This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations. APPROACH AND RESULTS: All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis. CONCLUSIONS: AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.

From Rain Tanks to Catchments: Use of Low-Impact Development To Address Hydrologic Symptoms of the Urban Stream Syndrome.

Catchment urbanization perturbs the water and sediment budgets of streams, degrades stream health and function, and causes a constellation of flow, water quality, and ecological symptoms collectively known as the urban stream syndrome. Low-impact development (LID) technologies address the hydrologic symptoms of the urban stream syndrome by mimicking natural flow paths and restoring a natural water balance. Over annual time scales, the volumes of stormwater that should be infiltrated and harvested can be estimated from a catchment-scale water-balance given local climate conditions and preurban land cover. For all but the wettest regions of the world, a much larger volume of stormwater runoff should be harvested than infiltrated to maintain stream hydrology in a preurban state. Efforts to prevent or reverse hydrologic symptoms associated with the urban stream syndrome will therefore require: (1) selecting the right mix of LID technologies that provide regionally tailored ratios of stormwater harvesting and infiltration; (2) integrating these LID technologies into next-generation drainage systems; (3) maximizing potential cobenefits including water supply augmentation, flood protection, improved water quality, and urban amenities; and (4) long-term hydrologic monitoring to evaluate the efficacy of LID interventions.

An evaluation of a bed instability index as an indicator of habitat quality in mountain streams of the northwestern United States.

Managers of aquatic resources benefit from indices of habitat quality that are reproducible and easy to measure, demonstrate a link between habitat quality and biota health, and differ between human-impacted (i.e., managed) and reference (i.e., nonimpacted or minimally impacted) conditions. The instability index (ISI) is an easily measured index that describes the instability of a streambed by relating the tractive force of a stream at bankfull discharge to the median substrate size. Previous studies have linked ISI to biological condition but have been limited to comparisons of sites within a single stream or among a small number of streams. We tested ISI as an indicator of human impact to habitat and biota in mountain streams of the northwestern USA. Among 1428 sites in six northwestern states, ISI was correlated with other habitat measures (e.g., residual pool depth, percent fine sediment) and indices of biotic health (e.g., number of intolerant macroinvertebrate taxa, fine sediment biotic index) and differed between managed and reference sites across a range of stream types and ecoregions. While ISI could be useful in mountain streams throughout the world, this index may be of particular interest to aquatic resource managers in the northwestern USA where a large dataset, from which ISI can be calculated, exists.

The direct renin inhibitor aliskiren localizes and persists in rat kidneys.

The aims of this study were to 1) determine whether renal localization of aliskiren and its antihypertensive and renoprotective effects persist after administration of the drug is stopped and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg·kg(-1)·day(-1) sc; osmotic minipumps) or enalapril (18 mg/l in drinking water). After a 2-wk treatment, dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for a 3-wk washout. One week of treatment with aliskiren and enalapril reduced blood pressure and albuminuria vs. baseline. After cessation of either treatment, blood pressure had returned to pretreatment levels and albuminuria remained relatively low for 1 wk, but rose thereafter similarly in both groups. In contrast, renal mRNA for transforming growth factor-ß and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 wk after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [(3)H]-aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days' washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor.

Renin inhibition reverses renal disease in transgenic mice by shifting the balance between profibrotic and antifibrotic agents.

Aliskiren, a direct renin inhibitor, is a novel antihypertensive drug. To study whether aliskiren can reverse chronic kidney disease, we administered it to renin transgenic mice, a strain characterized by elevated blood pressure and a slow decline of renal function, mimicking well the progression of hypertensive chronic kidney disease. Ten-month-old transgenic mice were treated either with aliskiren or placebo for 28 days. Age-matched wild-type mice treated or not with aliskiren were considered as normotensive controls. Aliskiren reduced blood pressure to wild-type levels from as early as day 14. Proteinuria and cardiac hypertrophy and fibrosis were also normalized. Renal interstitial fibrosis and inflammation were significantly ameliorated in aliskiren-treated mice (shown by the decrease of proinflammatory and profibrotic markers), and the phenotypes of tubular epithelial cells and podocytes were restored as evidenced by the reappearance of cellular proteins characteristic of normal phenotype of these cells. Profibrotic p38 and Erk mitogen-activated protein kinases were highly activated in placebo-treated transgenic animals. Aliskiren treatment cancelled this activation. This nephroprotection was not attributed to the antihypertensive activity of aliskiren, because blood pressure normalization after treatment with hydralazine failed to induce the regression of renal fibrosis. Direct inhibition of renin can restore renal function and structure in aged hypertensive animals with existing proteinuria. This finding suggests that, in addition to antihypertensive action, aliskiren can be also used to treat chronic kidney disease.

Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor.

Hyperglycaemia up-regulates intracellular AngII (angiotensin II) production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than ARBs (angiotensin receptor blockers) or ACEis (angiotensin-converting enzyme inhibitors). In the present study, we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACEi. Diabetes was induced in adult mice for 10 weeks by STZ (streptozotocin). Diabetic mice were treated with insulin, aliskiren (a renin inhibitor), benazeprilat (an ACEi) or valsartan (an ARB) via subcutaneous mini-pumps. Significant impairment in diastolic and systolic cardiac functions was observed in diabetic mice, which was completely prevented by all three RAS (renin-angiotensin system) inhibitors. Hyperglycaemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, whereas valsartan was partially effective. Diabetes increased cardiac PRR (prorenin receptor) expression and nuclear translocation of PLZF (promyelocytic zinc finger protein), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function to ARBs and ACEis. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines and PRR expression suggested subtle differences in their mechanisms of action.

Taking the "waste" out of "wastewater" for human water security and ecosystem sustainability.

Humans create vast quantities of wastewater through inefficiencies and poor management of water systems. The wasting of water poses sustainability challenges, depletes energy reserves, and undermines human water security and ecosystem health. Here we review emerging approaches for reusing wastewater and minimizing its generation. These complementary options make the most of scarce freshwater resources, serve the varying water needs of both developed and developing countries, and confer a variety of environmental benefits. Their widespread adoption will require changing how freshwater is sourced, used, managed, and priced.

Implementing AORN recommended practices for prevention of retained surgical items.

Retention of a surgical item is a preventable event that can result in patient injury. AORN's "Recommended practices for prevention of retained surgical items" emphasizes the importance of using a multidisciplinary approach for prevention. Procedures should include counts of soft goods, needles, miscellaneous items, and instruments, and efforts should be made to prevent retention of fragments of broken devices. If a count discrepancy occurs, the perioperative team should follow procedures to locate the missing item. Perioperative leaders may consider the use of adjunct technologies such as bar-code scanning, radio-frequency detection, and radio-frequency identification. Ambulatory and hospital patient scenarios are included to exemplify appropriate strategies for preventing retained surgical items.