A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration.

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.

Renin-Angiotensin-Aldosterone System Blockade after AKI with or without Recovery among US Veterans with Diabetic Kidney Disease.

SIGNIFICANCE STATEMENT: Among patients with CKD, optimal use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers after AKI is uncertain. Despite these medications' ability to reduce risk of mortality and other adverse outcomes, there is concern that ACEi/ARB use may delay recovery of kidney function or precipitate recurrent AKI. Prior studies have provided conflicting data regarding the optimal timing of these medications after AKI and have not addressed the role of kidney recovery in determining appropriate timing. This study in US Veterans with diabetes mellitus and proteinuria demonstrated an association between ACEi/ARB use and lower mortality. This association was more pronounced with earlier post-AKI ACEi/ARB use and was not meaningfully affected by initiating ACEis/ARBs before versus after recovery from AKI. BACKGROUND: Optimal use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) after AKI is uncertain. METHODS: Using data derived from electronic medical records, we sought to estimate the association between ACEi/ARB use after AKI and mortality in US military Veterans with indications for such treatment (diabetes and proteinuria) while accounting for AKI recovery. We used ACEi/ARB treatment after hospitalization with AKI (defined as serum creatinine ≥50% above baseline concentration) as a time-varying exposure in Cox models. The outcome was all-cause mortality. Recovery was defined as return to ≤110% of baseline creatinine. A secondary analysis focused on ACEi/ARB use relative to AKI recovery (before versus after). RESULTS: Among 54,735 Veterans with AKI, 31,146 deaths occurred over a median follow-up period of 2.3 years. Approximately 57% received an ACEi/ARB <3 months after hospitalization. In multivariate analysis with time-varying recovery, post-AKI ACEi/ARB use was associated with lower risk of mortality (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], 0.72 to 0.77). The association between ACEi/ARB use and mortality varied over time, with lower mortality risk associated with earlier initiation ( P for interaction with time <0.001). In secondary analysis, compared with those with neither recovery nor ACEi/ARB use, risk of mortality was lower in those with recovery without ACEi/ARB use (aHR, 0.90; 95% CI, 0.87 to 0.94), those without recovery with ACEi/ARB use (aHR, 0.69; 95% CI, 0.66 to 0.72), and those with ACEi/ARB use after recovery (aHR, 0.70; 95% CI, 0.67 to 0.73). CONCLUSIONS: This study demonstrated lower mortality associated with ACEi/ARB use in Veterans with diabetes, proteinuria, and AKI, regardless of recovery. Results favored earlier ACEi/ARB initiation.

CKD Progression Risk and Subsequent Cause of Death: A Population-Based Cohort Study.

Rationale & Objective: Chronic kidney disease (CKD) is a prevalent condition with high mortality rates. Cardiovascular disease (CVD) is accepted as the leading cause of death in CKD, but data are limited, and no study has evaluated the cause of death in those with progressive CKD versus stable kidney function. Study Design: Retrospective cohort. Setting & Participants: Adults receiving primary care at M Health Fairview (MHFV) after December 31, 2012, with linked Minnesota Death Index data before December 31, 2019, were included. A second cohort was created from adult participants in the 1996-2006 National Health and Nutrition Examination Survey (NHANES) linked with the National Death Index through 2015. Individuals with kidney replacement therapy at baseline were excluded. Exposures: Estimated glomerular filtration rate (eGFR) and proteinuria assessed at baseline defined the exposure categories for MHFV and NHANES. CKD progression in MHFV was also defined as an eGFR decrease ≥30% from baseline or incident kidney replacement therapy. Outcome: CVD-, malignancy-, and dementia-attributed death. Analytical Approach: Multinomial logistic regression. Results: For both cohorts, CVD death was more common than malignancy death for those with eGFR <60 mL/min/1.73 m2, whereas the converse was true for those with higher eGFR without proteinuria. In NHANES, CVD deaths were higher in those with proteinuria and eGFR ≥60 mL/min/1.73 m2. CKD progression in MHFV had a limited impact on the association with the cause of death except on dementia deaths, which were less common with progression at several stages of CKD. Proteinuria had limited impact on the association with the cause of death across a range of eGFR levels. Limitations: Limited follow-up and, for MHFV, nonprotocolized measures of kidney function were limitations, as were the intrinsic accuracy limitations for death certificates. Conclusions: CVD death is the most significant cause of death observed for those with a reduced eGFR irrespective of CKD progression.

Cis-regulatory basis of sister cell type divergence in the vertebrate retina.

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key cis-regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar cis-regulatory grammars, marked by enrichment of K50 homeodomain binding sites. However, cell class-specific enhancers are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. We show that converting K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific cis-regulatory elements was a critical step in the evolutionary divergence of the bipolar transcriptome from that of photoreceptors.

Trends in Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use among Those with Impaired Kidney Function in the United States.

BACKGROUND: Although hypertension is common in CKD and evidence-based treatment of hypertension has changed considerably, contemporary and nationally representative information about use of angiotensin-converting enzyme (ACEs) inhibitors or angiotensin II receptor blockers (ARBs) in CKD is lacking. METHODS: We examined ACE/ARB trends from 1999 to 2014 among 38,885 adult National Health and Nutrition Examination Survey participants with creatinine-based eGFR<60 ml/min per 1.73 m2 or urinary albumin-to-creatinine ratio ≥30 mg/g. RESULTS: Of 7085 participants with CKD, 34.9% used an ACE/ARB. Across four eras studied, rates of use rose significantly (rates were 25.5% in 1999-2002, 33.3% in 2003-2006, 39.0% in 2007-2010, and 40.1% in 2011-2014) but appeared to plateau after 2003. Among those with CKD, use was significantly greater among non-Hispanic white and black individuals (36.1% and 38.2%, respectively) and lower among Hispanic individuals (26.7%) and other races/ethnicities (29.3%). In age-, sex-, and race/ethnicity-adjusted models, ACE/ARB use was significantly associated with era (adjusted odds ratios [aOR], 1.41; 95% confidence interval [95% CI], 1.14 to 1.74 for 2003-2006, 1.84; 95% CI, 1.48 to 2.28 for 2007-2010, and 2.02; 95% CI, 1.61 to 2.53 for 2011-2014 versus 1999-2002); it also was significantly associated with non-Hispanic black versus non-Hispanic white race/ethnicity (aOR, 1.40; 95% CI, 1.19 to 1.66). Other multivariate associations included older age, men, elevated BMI, diabetes mellitus, treated hypertension, cardiac failure, myocardial infarction, health insurance, and receiving medical care within the prior year. CONCLUSIONS: Rates of ACE/ARB use increased in the early 2000s among United States adults with CKD, but for unclear reasons, use appeared to plateau in the ensuing decade. Research examining barriers to care and other factors is needed.

The impact of outpatient acute kidney injury on mortality and chronic kidney disease: a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) has been extensively studied in hospital settings. Limited data exist regarding outcomes for patients with outpatient AKI who are not subsequently admitted. We investigated whether outpatient AKI, defined by a 50% increase in creatinine (Cr), is associated with increased mortality and renal events. METHODS: In this retrospective study, outpatient serum Cr values from adults receiving primary care at a health system during an 18-month exposure period were used to categorize patients into one of five groups (no outpatient AKI, outpatient AKI with recovery, outpatient AKI without recovery, outpatient AKI without repeat Cr and no Cr). Principal outcomes of all-cause mortality and renal events (50% decline in estimated glomerular filtration rate to <30 mL/min/1.73 m2) were examined using Cox proportional hazards models. RESULTS: Among 384 869 eligible patients, 51% had at least one Cr measured during the exposure period. Outpatient AKI occurred in 1.4% of patients while hospital AKI occurred in only 0.3% of patients. The average follow-up was 5.3 years. Outpatient AKI was associated with an increased risk of all-cause mortality {adjusted hazard ratio [aHR] 1.90 [95% confidence interval (CI) 1.76-2.06]} and results were consistent across all AKI groups. Outpatient AKI was also associated with an increased risk of renal events [aHR 1.33 (95% CI 1.11-1.59)], even among those who recovered. CONCLUSIONS: Outpatient AKI is more prevalent than inpatient AKI and is a risk factor for all-cause mortality and renal events, even among those who recover kidney function. Further research is necessary to determine risk factors and identify strategies for preventing outpatient AKI.

Platelet count and associated morbidities in VLBW infants with pharmacologically treated patent ductus arteriosus.

OBJECTIVE: Characterize the diagnosis of PDA and the distribution of pretreatment platelet count in pharmacologically managed PDA in infants ≤1500 g and assess the relationship of platelet count to serious morbidities. STUDY DESIGN: This is a retrospective, observational study. In 40 hospitals, data were collected on PDA, including pretreatment platelet count. Distribution of platelet count was examined. The association of platelet count and clinical outcomes of IVH, NEC and PDA closure prior to discharge were examined. Chi-square test was used to compare outcomes by platelet count groups. RESULTS: There were 311 patients treated with medically treated PDA. Pretreatment platelet counts were categorized as 0-119 K, 120-199 K, 200-299 K, >300 K. Incidence and grade of IVH were not significantly different by platelet group. Across all groups: No IVH 62-83%, Grades 1-2 IVH 13-25%, Grades 3-4 IVH 2-13%. NEC occurred in 0-11% of all patients studied. PDA closure rate was 33-45%. CONCLUSION: PDA closure was not significantly affected by platelet count. Platelet count was not a statistically significant factor for development of IVH and NEC in infants born <1500 g with pharmacologically treated PDA.

Timing of preemptive vascular access placement: do we understand the natural history of advanced CKD?: an observational study.

BACKGROUND: Little is known about the targets and expectations of practicing nephrologists with regard to timing of preemptive AV access surgery and how these relate to actual observed practice patterns in clinical care. METHODS: We administered a 8-question survey to assess nephrologists' expectations for preemptive vascular access placement to 53 practicing nephrologists in California. We performed a retrospective chart review of 116 patients who underwent preemptive vascular access placement at a large academic medical center and examined progression to ESRD. RESULTS: According to our survey of nephrologists, most aimed to have preemptive vascular access created about 6 months prior to start of ESRD or when the chances of ESRD within the next year is two-thirds or greater. The estimated GFR level at which they believe match these conditions is approximately 18 ml/min/1.73 m2. Among the 116 patients with CKD who underwent preemptive vascular access creation, the mean estimated GFR at the time of access creation was 16.1 (6.8) ml/min/1.73 m2. Only 57 out of the 116 patients (49.1%) patients initiated maintenance HD within 1 year after surgery. CONCLUSIONS: In our study, most nephrologists aim for preemptive vascular access surgery approximately 6 months prior to the start of HD. However in fact, only approximately 50% of patients who underwent preemptive vascular access surgery started HD within 1 year. Better tools are needed to predict the natural history of advanced CKD.

Estimating glomerular filtration rate: is it good enough? And is it time to move on?

PURPOSE OF REVIEW: The aim is to examine a dominant narrative in nephrology over the past decade: that measured glomerular filtration rate (GFR) is the gold standard measure of kidney function; accurate assessment of GFR is critical and paramount; and further efforts to refine GFR estimation should continue. RECENT FINDINGS: Studies that have simultaneously compared measured GFR and estimated GFR (using endogenous filtration markers such as creatinine, or newer ones such as cystatin C or ß-trace protein) against some external metric of kidney function have failed to show that measured GFR is consistently superior, which is what one would expect if measured GFR were truly the 'gold standard.' SUMMARY: Compared with estimated GFR, measured GFR does not consistently predict renal-related outcomes better. Clinical decision-making almost never requires precise and accurate knowledge of a patient's static GFR value. Efforts at perfecting cross-sectional estimates of GFR may have reached a point of diminishing returns.

A Cenozoic record of the equatorial Pacific carbonate compensation depth.

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

How many struggle to get by in retirement?

PURPOSE: This study compared the official poverty rate for adults aged 65 years and older with alternative measures that portray the true resources and needs of older adults. DESIGN AND METHODS: The analysis used data from the 2004 Health and Retirement Study on income, assets, in-kind transfers, and out-of-pocket medical expenses. It also incorporated the effects of federal and state income taxes on net incomes, and accounted for the potential annuity value of assets in measuring resources. RESULTS: The alternative poverty measures that account for out-of-pocket health spending estimate that between 0.3 and 1.5 million more older adults live in poverty than acknowledged by the official measure. IMPLICATIONS: These results highlight the need to update poverty measures so that they better reflect older adults' circumstances. This will become increasingly important as policymakers consider reforms to improve solvency in the Social Security and Medicare programs that may require benefit cuts or increased cost sharing.