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Canagliflozin Reduces Kidney-Related Adverse Events in Type 2 Diabetes and CKD: Findings From the Randomized CREDENCE Trial

Heerspink, Hiddo J L; Oshima, Megumi; Zhang, Hong; Li, Jingwei; Agarwal, Rajiv; Capuano, George; Charytan, David M; Craig, Jagriti; de Zeeuw, Dick; Di Tanna, Gian Luca; Levin, Adeera; Neal, Bruce; Perkovic, Vlado; Wheeler, David C; Yavin, Yshai; Jardine, Meg J
RATIONALE AND OBJECTIVE/OBJECTIVE:Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN/METHODS:A randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING AND PARTICIPANTS/METHODS:4,401 trial participants with T2DM, CKD, and urinary albumin:creatinine ratio >300-5000mg/g. INTERVENTIONS/METHODS:Participants were randomly assigned to receive canagliflozin 100mg/day or placebo. OUTCOMES/RESULTS:). RESULTS:, respectively; P-interaction=0.3), with similar results for AKI (P-interaction=0.9). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio: 2.2 [95% CI: 1.0, 4.7]; P=0.04). LIMITATIONS/CONCLUSIONS:Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured and creatinine data after an AKI event were not available for all participants. CONCLUSION/CONCLUSIONS:Canagliflozin compared to placebo was associated with a reduced incidence of serious and non-serious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney disease events.
PMID: 34029680
ISSN: 1523-6838
CID: 4902992

Quality and Safety Outcomes of a Hospital Merger Following a Full Integration at a Safety Net Hospital

Wang, Erwin; Arnold, Sonia; Jones, Simon; Zhang, Yan; Volpicelli, Frank; Weisstuch, Joseph; Horwitz, Leora; Rudy, Bret
Importance/UNASSIGNED:Hospital consolidations have been shown not to improve quality on average. Objective/UNASSIGNED:To assess a full-integration approach to hospital mergers based on quality metrics in a safety net hospital acquired by an urban academic health system. Design, Setting, and Participants/UNASSIGNED:This quality improvement study analyzed outcomes for all nonpsychiatric, nonrehabilitation, non-newborn patients discharged between September 1, 2010, and August 31, 2019, at a US safety net hospital that was acquired by an urban academic health system in January 2016. Interrupted time series and statistical process control analyses were used to assess the main outcomes and measures. Data sources included the hospital's electronic health record, Centers for Medicare & Medicaid Services Hospital Compare, and nursing quality reports. Exposures/UNASSIGNED:A full-integration approach to the merger that included: (1) early administrative and clinical leadership integration with the academic health system; (2) rapid transition to the academic health system electronic health record; (3) local ownership of quality metrics; (4) system-level goals with real-time actionable analytics through combined dashboards; and (5) implementation of value-based and other analytic-driven interventions. Main Outcomes and Measures/UNASSIGNED:The primary outcome was in-hospital mortality. Secondary outcomes included 30-day readmission, patient experience, and hospital-acquired conditions. Results/UNASSIGNED:The 122 348 patients in the premerger (September 2010 through August 2016) and the 58 904 patients in the postmerger (September 2016 through August 2019) periods had a mean (SD) age of 55.5 (22.0) years; the total sample of 181 252 patients included 112 191 women (61.9%), the payor mix was majority governmental (144 375 patients [79.7%]), and most admissions were emergent (121 469 patients [67.0%]). There was a 0.71% (95% CI, 0.57%-0.86%) absolute (27% relative) reduction in the crude mortality rate and 0.95% (95% CI, 0.83%-1.12%) absolute (33% relative) in the adjusted rate by the end of the 3-year intervention period. There was no significant improvement in readmission rates after accounting for baseline trends. There were fewer central line infections per 1000 catheter days, fewer catheter-associated urinary tract infections per 1000 discharges, and a higher likelihood of patients recommending the hospital or ranking it 9 or 10. Conclusions and Relevance/UNASSIGNED:In this quality improvement study, a hospital merger with a full-integration approach to consolidation was found to be associated with improvement in quality outcomes.
PMID: 34989794
ISSN: 2574-3805
CID: 5107272

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial

Katz, Ira R; Rogers, Malcolm P; Lew, Robert; Thwin, Soe Soe; Doros, Gheorghe; Ahearn, Eileen; Ostacher, Michael J; DeLisi, Lynn E; Smith, Eric G; Ringer, Robert J; Ferguson, Ryan; Hoffman, Brian; Kaufman, James S; Paik, Julie M; Conrad, Chester H; Holmberg, Erika F; Boney, Tamara Y; Huang, Grant D; Liang, Matthew H
Importance/UNASSIGNED:Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective/UNASSIGNED:To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants/UNASSIGNED:This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions/UNASSIGNED:Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures/UNASSIGNED:Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results/UNASSIGNED:The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance/UNASSIGNED:In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration/ Identifier: NCT01928446.
PMID: 34787653
ISSN: 2168-6238
CID: 5049172

Hypernatremia in the intensive care unit

Chand, Raja; Chand, Ranjeeta; Goldfarb, David S
PURPOSE OF REVIEW/OBJECTIVE:Hypernatremia is a relatively frequent electrolyte disorder seen in critically ill patients. As many as 27% of patients in intensive care units (ICUs) develop hypernatremia of variable severity during an ICU stay. Debate among specialists often ensues as to whether to correct hypernatremia or not. Some practitioners, particularly intensivists, believe that correction of hypernatremia with fluids may cause expansion of the extracellular fluid volume (ECFV) thereby worsening ventilation and impeding extubation. Other practitioners, including many nephrologists, do not expect correction of hypernatremia to lead to clinically apparent ECFV expansion, and fear other deleterious effects of hypernatremia. In this review we address the controversy regarding appropriate practice. FINDINGS/RESULTS:There are no randomized, clinical trials (RCTs) to guide the administration of electrolyte-free fluid administration in hypernatremic patients. However, there are associations, demonstrated in the literature, suggesting that hypernatremia of any severity will increase the mortality and length of stay in these patients. These associations generally support the practice of correction of hypernatremia. In addition, our knowledge of the distribution of total body water influences us towards correcting hypernatremia as an appropriate therapy. We do not expect that adequate RCTs addressing this question will be performed. SUMMARY/CONCLUSIONS:Allowing persistence of any degree of hypernatremia is associated with increased mortality, length of stay (LOS) and postdischarge mortality. We expect that proper use of electrolyte-free water intake will avoid adverse outcomes.
PMID: 34939612
ISSN: 1473-6543
CID: 5109022

Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

Neuen, Brendon L; Oshima, Megumi; Perkovic, Vlado; Agarwal, Rajiv; Arnott, Clare; Bakris, George; Cannon, Christopher P; Charytan, David M; Edwards, Robert; Górriz, Jose L; Jardine, Meg J; Levin, Adeera; Neal, Bruce; De Nicola, Luca; Pollock, Carol; Rosenthal, Norman; Wheeler, David C; Mahaffey, Kenneth W; Heerspink, Hiddo J L
AIMS /UNASSIGNED:Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS /UNASSIGNED:The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. CONCLUSION /UNASSIGNED:Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.
PMID: 34423370
ISSN: 1522-9645
CID: 5086882

Controlled Study of Decision-Making Algorithms for Kidney Replacement Therapy Initiation in Acute Kidney Injury

Kelly, Yvelynne; Mistry, Kavita; Ahmed, Salman; Shaykevich, Shimon; Desai, Sonali; Lipsitz, Stuart; Leaf, David; Mandel, Ernest; Robinson, Emily; McMahon, Gearoid; Czarnecki, Peter; Charytan, David; Waikar, Sushrut; Mendu, Mallika
BACKGROUND:Acute kidney injury (AKI) requiring kidney replacement therapy (KRT) is associated with high mortality and utilization. We evaluated the use of an AKI-Standardized Clinical Assessment and Management Plan (SCAMP) on patient outcomes including mortality, hospital and ICU length of stay. METHODS:We conducted a 12-month controlled study in the ICUs of a large academic tertiary medical center. We alternated use of the AKI-SCAMP with use of a "sham" control form in 4-6-week blocks. The primary outcome was risk of inpatient mortality. Pre-specified secondary outcomes included 30-day mortality, 60-day mortality and hospital and ICU length of stay. Generalized estimating equations were used to estimate the impact of the AKI-SCAMP on mortality and length of stay. RESULTS:There were 122 patients in the AKI-SCAMP group and 102 patients in the control group. There was no significant difference in inpatient mortality associated with AKI-SCAMP use (41% vs 47% control). AKI-SCAMP use was associated with significantly reduced ICU length of stay (mean 8 (95% CI 8-9) vs 12 (95% CI 10-13) days; p = <0.0001) and hospital length of stay (mean 25 (95% CI 22-29) vs 30 (95% CI 27-34) days; p = 0.02). Patients in the AKI-SCAMP group less likely to receive KRT in the context of physician-perceived treatment futility than those in the control group (2% vs 7%, p=0.003). CONCLUSIONS:Use of the AKI-SCAMP tool for AKI-KRT was not significantly associated with inpatient mortality but was associated with reduced ICU and hospital length of stay and use of KRT in cases of physician-perceived treatment futility.
PMID: 34911731
ISSN: 1555-905x
CID: 5086912

Arteriovenous Fistula Maturation, Functional Patency, and Intervention Rates

Huber, Thomas S; Berceli, Scott A; Scali, Salvatore T; Neal, Dan; Anderson, Erik M; Allon, Michael; Cheung, Alfred K; Dember, Laura M; Himmelfarb, Jonathan; Roy-Chaudhury, Prabir; Vazquez, Miguel A; Alpers, Charles E; Robbin, Michelle L; Imrey, Peter B; Beck, Gerald J; Farber, Alik M; Kaufman, James S; Kraiss, Larry W; Vongpatanasin, Wanpen; Kusek, John W; Feldman, Harold I
Importance/UNASSIGNED:National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective/UNASSIGNED:To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, Setting, and Participants/UNASSIGNED:The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions/UNASSIGNED:All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main Outcomes and Measures/UNASSIGNED:In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results/UNASSIGNED:Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and Relevance/UNASSIGNED:The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.
PMID: 34550312
ISSN: 2168-6262
CID: 5026862

Solid-Phase C1q/C3d Fixing Readouts Correlate with High Median Fluorescence Intensity (MFI) De Novo Donor-Specific HLA Antibodies and C4d⁺ Antibody-Mediated Rejection in Kidney Transplant Recipients

Tatapudi, Vasishta S; Kopchaliiska, Dessislava; da Gente, Gilberto J; Buenaventura, Owen F; Singh, Manpreet; Laszik, Zoltan; Adey, Deborah B; Rajalingam, Raja
BACKGROUND Solid-phase assays to investigate the complement-activating capacity of HLA antibodies have been utilized to optimize organ allocation and improve transplant outcomes. The clinical utility of C1q/C3d-binding characteristics of de novo donor-specific anti-HLA antibodies (dnDSA) associated with C4d-positive antibody-mediated rejection (C4d⁺ AMR) in kidney transplants (KTx) has not been defined. MATERIAL AND METHODS Sera from 120 KTx recipients that had dnDSA concurrent with protocol/cause biopsy (median 3.8 years after transplantation) were screened for C1q and C3d-binding dnDSA. The difference in the incidence of C4d⁺ AMR between recipients with and without C1q/C3d-binding dnDSA was assessed. RESULTS Over 86% of dnDSAs were class II antibodies. The immunodominant dnDSAs characterized by the highest median fluorescence intensity (MFI) in most recipients were HLA-DQ antibodies (67%). Most recipients (62%, n=74) had either C1q⁺ (56%), C3d⁺ (48%), or both C1q⁺C3d⁺ (41.2%) dnDSA, while the remaining 38% were negative for both C1q and C3d. Of those with C1q⁺/C3d⁺ dnDSA, 87% had high-MFI IgG (MFI=14144±5363 and 13932±5278, respectively), while 65% of C1q⁻C3d⁻ dnDSA had low-MFI IgG (MFI=5970±3347). The incidence of C4d+ AMR was significantly higher in recipients with C1q⁺ (66%), C3d+ (74%), and C1q⁺C3d⁺ (72%) dnDSA than in those with C1q⁻C3d⁻ dnDSA (30%) recipients. Recipients with C3d⁺/C1q⁺ dnDSA had higher C4d⁺ scores on biopsy. CONCLUSIONS C1q⁺/C3d⁺ dnDSA were associated with C4d⁺ AMR and high-IgG MFI. Our data call into question the predictive utility of C1q/C3d-binding assays in identifying KTx recipients at risk of allograft failure. In conclusion, IgG MFI is sufficient for clinical management, and the C1q/C3d-assays with added cost do not provide any additional information.
PMID: 34848674
ISSN: 2329-0358
CID: 5069072

Cystinuria: an update on pathophysiology, genetics, and clinical management

D'Ambrosio, Viola; Capolongo, Giovanna; Goldfarb, David; Gambaro, Giovanni; Ferraro, Pietro Manuel
Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.
PMID: 34812923
ISSN: 1432-198x
CID: 5063522

Protocolized Urine Sampling is Associated with Reduced Catheter-Associated Urinary Tract Infections: A Pre- and Post-intervention Study

Frontera, Jennifer A; Wang, Erwin; Phillips, Michael; Radford, Martha; Sterling, Stephanie; Delorenzo, Karen; Saxena, Archana; Yaghi, Shadi; Zhou, Ting; Kahn, D Ethan; Lord, Aaron S; Weisstuch, Joseph
BACKGROUND:Standard urine sampling and testing techniques do not mitigate against detection of colonization, resulting in false positive catheter-associated urinary tract infections (CAUTI). We aim to evaluate if a novel protocol for urine sampling and testing reduces rates of CAUTI. METHODS:A pre-intervention and post-intervention study with a contemporaneous control group was conducted at two campuses (test and control) of the same academic medical center. The test campus implemented a protocol requiring urinary catheter removal prior to urine sampling from a new catheter or sterile straight catheterization, along with urine bacteria and pyuria screening prior to culture. Primary outcomes were test campus CAUTI rates compared between each 9-month pre- and post-intervention epoch. Secondary outcomes included the percent reductions in CAUTI rates compared between the test campus and a propensity-score matched cohort at the control campus. RESULTS:  A total of 7,991 patients from the test campus were included in the primary analysis, and 4,264 were included in the propensity-score matched secondary analysis. In primary analysis, CAUTI/1000-patients was reduced by 77% (6.6 to 1.5), CAUTI/1000-catheter days by 63% (5.9 to 2.2) and urinary catheter days/patient by 37% (1.1 to 0.69, all P≤0.001). In propensity score-matched analysis, CAUTI/1000-patients was reduced by 82% at the test campus versus 57% at the control campus, CAUTI/1000 catheter-days declined by 68% versus 57% and catheter-days/patient decreased by 44% versus 1% (all P<0.001). CONCLUSIONS: Protocolized urine sampling and testing aimed at minimizing contamination by colonization was associated with significantly reduced CAUTI infection rates and urinary catheter days.
PMID: 32776142
ISSN: 1537-6591
CID: 4556052