A System-Wide Population Health Value Approach to Reduce Hospitalization Among Chronic Kidney Disease Patients: an Observational Study.

BACKGROUND: Chronic kidney disease (CKD) is a leading cause of healthcare morbidity, utilization, and expenditures nationally, and caring for late-stage CKD populations is complex. Improving health system efficiency could mitigate these outcomes and, in the COVID-19 era, reduce risks of viral exposure. OBJECTIVE: As part of a system-wide transformation to improve healthcare value among populations with high healthcare utilization and morbidity, UCLA Health evaluated a new patient-centered approach that we hypothesized would reduce inpatient utilization for CKD patients. DESIGN: For 18 months in 2015-2016 and 12 months in 2017, we conducted an interrupted time series regression analysis to evaluate the intervention's impact on inpatient utilization. We used internal electronic health records and claims data across six payers. PARTICIPANTS: A total of 1442 stage 4-5 CKD patients at a large academic medical center. INTERVENTION: Between October and December 2016, the organization implemented a Population Health Value CKD intervention for the CKD stages 4-5 population. A multispecialty leadership team risk stratified the population and identified improvement opportunities, redesigned multispecialty care coordination pathways across settings, and developed greater ambulatory infrastructure to support care needs. MAIN MEASURES: Outcomes included utilization of hospitalizations, emergency department (ED) visits, inpatient bed days, and 30-day all-cause readmissions. KEY RESULTS: During the 12 months following intervention implementation, the monthly estimated rate of decline for hospitalizations was 5.4% (95% CI: 3.4-7.4%), which was 3.4 percentage points faster than the 18-month pre-intervention decline of 2.0% (95% CI: 1.0-2.2%) per month (p = 0.004). Medicare CKD patients' monthly ED visit rate of decline was 3.0% (95% CI: 1.2-4.8%) after intervention, which was 2.6 percentage points faster than the pre-intervention decline of 0.4% (95% CI: - 0.8 to 1.6%) per month (p = 0.02). CONCLUSIONS: By creating care pathways that link primary and specialty care teams across settings with increased ambulatory infrastructure, healthcare systems have potential to reduce inpatient healthcare utilization.

JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.

CD4(+) T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)-17 cells increased. We also describe a functional 'silencing' of T helper cells both in vivo and in vitro and a blockade of pro-inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.

Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.

Advances in pathogenetic mechanisms of diabetic nephropathy.

The diabetic epidemic that is being experienced around the world has many ramifications. Since diabetes is the most common cause of end stage renal disease in the United States and the Western world, we can expect the increase in prevalence to continue. Minority individuals with diabetes suffer a disproportionately high incidence of diabetic nephropathy leading to end stage renal disease. The data suggest that aggressive medical management should be their mainstay of therapy. In the past five years, our knowledge of the mechanisms involved in the pathology of diabetic glomerulosclerosis has greatly expanded. Transforming growth factor (TGF)-beta still maintains a key role in the pathogenesis. However, many of the signaling mechanisms have now been described. Furthermore, TGF-beta may also function to damage glomerular epithelial cells or podocytes, resulting in podocyteuria and proteinuria that worsen with progressive diabetic nephropathy. Additionally, TGF-beta upregulation in diabetes may cause injury or transformation of tubular epithelial cells that contribute to interstitial fibrosis. The use of thiazolidinediones in type 2 diabetes is associated with improvement in insulin sensitivity, as well as improvement in albuminuria. The mechanisms by which these ligands function remain unclear, but there may be several targets that could include mesangial cells and podocytes.

Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells.

P:eroxisome proliferator-activated receptor-gamma (PPARgamma) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARgamma are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARgamma message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARgamma response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARgamma is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARgamma-PPRE protein complex, confirming specificity of binding of the PPARgamma to the PPRE. PPARgamma ligands rosiglitazone (1 to 10 micromol/L) and troglitazone (1 to 10 micromol/L) inhibited platelet-derived growth factor-induced DNA synthesis, measured as bromodeoxyuridine incorporation (P<0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 microgram urinary albumin/mg creatinine, P:<0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARgamma activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.

Syndrome X following renal transplantation.

The cardiovascular risk factors that accompany postrenal transplantation include an atherogenic lipid profile, hypertension, new-onset diabetes mellitus, and a chronic prothrombotic state. This picture describes the dysmetabolic syndrome or syndrome X, which can significantly aggravate not only the risk of cardiovascular disease and death in this population, but also the progression of allograft dysfunction. The recognition and aggressive management of the dysmetabolic syndrome in postrenal allograft recipients may have a favorable impact on the incidence of cardiovascular morbidity and mortality in these patients and prolong allograft function.

Cardiac expression of the Na(+)/Ca(2+) exchanger NCX1 is GATA factor dependent.

The cardiac sarcolemmal Na(+)/Ca(2+) exchanger plays a primary role in Ca(2+) efflux and is important in regulating intracellular Ca(2+) and beat-to-beat contractility. Of the three Na(+)/Ca(2+) exchanger genes cloned (NCX1, NCX2, and NCX3), only NCX1 is expressed in cardiac myocytes. NCX1 has alternative promoters for heart, kidney, and brain tissue-specific transcripts. Analysis of the cardiac NCX1 promoter (at -336 bp) identified a cardiac-specific minimum promoter (at -137) and two GATA sites (at -75 and -145). In this study, gel shift and supershift analyses identified GATA-4 in primary neonatal cardiac myocytes. Site-directed mutagenesis of the GATA-4 site at -75 abolishes binding and reduces activity of the minimum and full-length promoters by >90 and approximately 60%, respectively. Mutation of the GATA site at -145 reduces activity of the full-length promoter by approximately 30%. Mutation of an E-box at -175 does not alter promoter activity.

Lipid disorders in obesity.

Obesity is considered a public health problem because it is associated with multiple risk factors that place individuals into a significantly high risk group for coronary heart disease. The cardiovascular dysmetabolic syndrome seen in conjunction with obesity is not only associated with insulin resistance and hypertension but also involves an abnormal metabolism of lipids, which leads to an increased storage of fat and subsequent increase in the atherogenesis process. This article details the dyslipidemia of obesity and its cardiovascular consequences and presents some ways in which it can be managed.

Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+ exchanger gene.

Many studies have investigated the regulation of the Na+/ Ca2+ exchanger, NCX1, but limited data exist on transcriptional regulation of the NCX1 gene. We have identified the transcription start sites of three tissue-specific alternative promoters of NCX1 transcripts from rat heart, kidney, and brain. We have characterized the cardiac NCX1 promoter, from which the most abundant quantities of NCX1 transcripts are expressed. Transfection of primary cardiac myocytes, CHO cells, and COS-7 cells with overlapping genomic DNA fragments spanning the NCX1 cardiac transcription start site has uncovered a cardiac cell-specific minimum promoter from -137 to +85. The cardiac NCX1 promoter is TATA-less but has putative binding sites for cardiac-specific GATA factors, an E box, and an Inr as well as multiple active enhancers. The kidney NCX1 promoter has a typical TATA box and binding sites for several tissue-specific factors. The brain NCX1 promoter is very GC-rich and possesses several Sp-1 binding sites consistent with its ubiquitous expression.