Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium–glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels. The prevalence of diabetes mellitus has reached epidemic proportions worldwide . At the 2, and urine albumin-to-creatinine ratio (UACR) 300 mg/g Cr. Their good renoprotective effect may be due to the decrease in elevated intraglomerular pressure. They moderately lower the risk of albuminuria and reduce progression from CKD to ESRD [Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which are RAAS blockers, demonstrated benefits in preventing CKD progression and are, therefore, considered as first-line antihypertensive drugs in patients with diabetes mellitus, hypertension, eGFR 60 mL/min/1.73 m to ESRD ,12. EvenThe conventional treatments to maintain blood glucose levels do not always prevent DKD . On the The aim of this narrative review was to summarize the current knowledge on the role of SGLT2 inhibitors in the treatment of DKD and various physiological, clinical, and genetic factors that may influence the treatment outcomes.The pathophysiology of DKD is mostly driven by elevated reactive oxygen species (ROS) caused by prolonged hyperglycemia . The maiα) may also be involved in the development and progression of DKD [κB (NF-κB) is another factor that is important in inflammation. This is a ubiquitous transcription factor that could be triggered by hyperglycemia or AGEs. An increasing body of evidence suggests that JAK-STAT (Janus kinase (JAK)-signal transducer and activator of transcription (STAT)) regulates the major pathway for processing inflammatory signals and plays a key role in the pathogenesis of DKD. As the disease progresses, tubulointerstitial expression of a variety of JAK and STAT isoforms increases, and this expression is inversely related to eGFR. The JAK-STAT pathway triggers expression of intracellular cytokines, which function as a bridge between the paracrine stimulation system and nuclear receptors. In addition, cytokines and hyperglycemia can activate key mechanisms that regulate cell activation, proliferation, recruitment, migration, and differentiation [α and PKC-β isoforms activation was associated with increased NADPH activity and production of NADPH-dependent superoxide [β) lead to synthesis of the mesangial matrix. The increased levels of angiotensin II also activate NADPH oxidase, which increases ROS production in the kidney. On the other hand, TGF-β stimulates cellular differentiation and proliferation, hormone secretion, immune function, and is responsible for excessive remodeling of the extracellular matrix in the mesangium and for increased fibrotic processes in the tubular interstitial space [α expression in the epithelial cells of the proximal tubule and glomerulus enhances the expression of cytokines that act on cell survival, proliferation, adhesions, inflammatory responses, and apoptosis [α may decrease GFR and causes vasoconstriction due to increased endothelin-1 (ET-1) production and also impairs the glomerular filtration barrier and proteinuria.IL-18, IL-6, and tumor necrosis factor  are solute carriers facilitating glucose transport. Among the six SGLTs transporters, SGLT2 is responsible for 90% of glucose reabsorption and also for the majority of sodium reabsorption in kidneys. It has a low affinity and high capacity for glucose and is expressed in the brush border membrane of the S1 segment in the kidney cortex . Many paDespite the fact that glucosuria reduces the mean plasma glucose concentrations and ameliorates glucotoxicity, resulting in improved cell function and insulin sensitivity , it is kIt needs to be pointed out that T2DM alone may also be an independent risk factor for acute kidney injury (AKI). AKI is more frequent in T2DM patients when they are undergoing surgery, taking some specific medications, or have sepsis or septic shock. On the other hand, AKI may also manifest as acute exacerbation of DKD. There has been a continuous concern about potential negative effects of SGLT2 inhibitors on the risk and prognosis of AKI due to the changes in kidney function associated with their usage, such as significant hypovolemia and different types of diabetic ketoacidosis (DKA). However, the results from clinical trials, observational studies, and meta-analyses have consistently shown no increase in the risk of AKI or negative effects of AKI associated with SGLT2 inhibitors. On the contrary, SGLT2 inhibitors were reported to reduce the risk of AKI by 30–40% . In termSeveral large clinical trials investigated clinical outcomes of treatment with SGLT2 inhibitors; however, kidney outcomes were mostly evaluated as secondary endpoints . On the 2, albuminuria (30–500 mg/mmol), and were randomized into a canagliflozin or placebo group. The composite outcome included either ESKD  or a doubling of serum creatinine level from baseline (average of randomization and prerandomization) sustained for at least 30 days, or a death caused by kidney or cardiovascular disease. The study was stopped early because of clearly demonstrated superiority of canagliflozin, showing a 30% relative reduction in the primary kidney outcome by canagliflozin . In addition, there was significant evidence of benefits in regard to the secondary outcome of kidney transplant, dialysis, or kidney-related mortality  [The CREDENCE  study was the first double-blind, randomized, placebo-controlled clinical trial that included 4401 patients with T2DM and albuminuric CKD treated with ACE inhibitors or ARBs. All subjects had HbA1c levels from 6.5 to 12.0%, eGFR of 30 to <90 mL/min per 1.73 m54–0.97) . Two dou54–0.97) .2, kidney failure, and death from cardiovascular or kidney cause was 4.3% in patients on dapagliflozin and 5.6% in the placebo group  [p = 0.17) [2 who were on a stable dose of ACE inhibitors or ARBs. The patients were randomized into three treatment arms: 145 were treated with dapagliflozin, 155 with dapagliflozin and saxagliptin, and 148 received a placebo and were followed up every 4 weeks. Within the entire study period, reduced UACR was observed in the dapagliflozin and also in the dapagliflozin–saxagliptin arm. At the end of the study, which lasted 24 weeks, the difference in the mean UACR change from baseline was −21% (p = 0.011) in the dapagliflozin and −38% (p < 0.0001) in the dapagliflozin–saxagliptin arm. Furthermore, eGFR reductions were also observed at the end of the study, with differences in the mean change from baseline of –2.4 mL/min per 1·73 m2 (p = 0.011) in the dapagliflozin arm and –2.4 mL/min per 1.73 m2 (p = 0.0075) in the dapagliflozin–saxagliptin arm when compared to placebo [The DECLARE-TIMI 58  study was predominantly designed to evaluate the cardiovascular safety of dapagliflozin. The composite outcome consisting of a ≥40% decrease in eGFR to <60 mL/min per 1.73 m = 0.17) . The DEL placebo .2, or an eGFR of ≥45 to <90 mL/min per 1.73 m2 with UACR of at least 200 mg/g. Patients with or without T2DM treated with ACE inhibitors or ARBs were randomized into two groups. The patients in the first group were receiving 10 mg of empagliflozin, while the patients in the other group were receiving a placebo. The primary outcome was a composite of death from kidney or cardiovascular causes, ESKD, a persistent decline in eGFR <10 mL/min per 1.73 m2, and a sustained decline in eGFR of less than 40% from the baseline. The progression of kidney disease or death from cardiovascular causes appeared in 13.1% of the patients on empagliflozin and in 16.9% of the patients in the placebo group . There were no significant differences between both groups regarding the composite outcome of hospitalization for heart failure, death from cardiovascular causes, or death from any cause. However, the rate of hospitalization from any cause was lower in the empagliflozin group compared to the placebo group . Both groups experienced equal rates of major adverse events [EMPA-KIDNEY (Study of Heart and Kidney Protection With Empagliflozin) was also a double-blind, randomized, placebo-controlled study with a median duration of 2 years, which included 6600 patients with CKD and eGFR of ≥20 to <45 mL/min per 1.73 me events . The EMPe events .p < 0.001). Furthermore, patients treated with empagliflozin had a lower risk of serious kidney outcome [p < 0.001) [The EMPEROR-Reduced  study included 3730 patients with/without T2DM and heart failure with an ejection fraction of 40% or less who had appropriate treatment for heart failure. The median follow-up at 21 months showed that annual reduction in eGFR was slower in the empagliflozin group than in the placebo group ( outcome . The EMP< 0.001) . In the < 0.001) .The VERTIS-CV  study included T2DM patients treated with ertugliflozin or a placebo. Although UACR was reduced, the study did not observe significant changes in composite kidney outcomes. eGFR was reduced after ertugliflozin treatment, but the values returned to baseline and were higher after 104 weeks .2) that were randomized into two study arms: 5292 were treated with sotagliflozin and 5292 received a placebo. Although this study was primarily designed to assess cardiovascular safety, the secondary end points included a composite kidney outcome of the first occurrence of a sustained decrease of ≥50% in the eGFR from baseline for ≥30 days, long-term dialysis, kidney transplantation, or sustained eGFR of <15 mL/min/1.73 m2 for ≥30 days. The kidney outcomes did not differ significantly between the two groups [The SCORED  study included a total of 10.584 T2DM patients with CKD . Rare loss-of-function SLC5A2 mutations were associated with familial renal glucosuria, a benign condition characterized by decreased renal glucose reabsorption and increased glucose excretion in the presence of normal blood glucose levels [SLC5A2, with the initial studies suggesting their influence on glucose homeostasis in non-diabetic subjects [SLC5A2 rs9934336 was significantly associated with increased fasting blood glucose levels and HbA1c levels. This polymorphism was also significantly associated with higher risk for diabetic retinopathy, but not with DKD risk [SLC5A2 polymorphisms with the metabolic traits of T2DM patients nor with their response to treatment with empagliflozin [SGLT2 expression levels and activity may be directly related to genetic variability in its coding gene e levels . Severalsubjects . We haveDKD risk . Anotherliflozin .When considering the broader genetic background that may influence the response to SGLT2 inhibitors, one may first focus on the interaction of the treatment with the molecular mechanisms of the disease itself and, next, its complications. Genome-wide association studies (GWAS) enabled identification of more than 300 genetic susceptibility loci associated with T2DM (recently reviewed in ). HoweveIdentification of the susceptible loci associated with CKD risk may support early identification of T2DM patients at increased risk, while identification of SGLT2 inhibitors targets may support targeted therapeutic interventions through the analysis of a panel of genetic markers. The challenge of translating the risk loci identified by GWAS into clinical practice was solved by the introduction of the polygenic risk score (PRS), which presents the weighted sum of risk alleles, taking into account their effect sizes . With thThe limitations of the GWAS approaches in their ability to capture only common genetic variations with a frequency ≥1% may be overcome by whole-exome or whole-genome sequencing that have the potential of detecting rare genetic variants, among them also variants with potentially larger effect sizes, that may contribute to CKD .The observation of pleiotropic effects of SGLT2i on both heart and kidney failure led to the search for overlapping genetic backgrounds between these two late complications and for the potential common targets of SGLT2 inhibitors. Li et al. used canonical correlation analysis based on multivariate regression analysis on the summary statistics data from two large independent meta-analyses of GWAS. This led to identification of 4624 SNPs and 1745 genes associated with CKD and heart failure (HF). The identified genes were validated against the transcriptome-wide gene expression data for CKD and HF. Next, gene enrichment and KEGG pathway analyses were used to explore the potential functional significance of the identified genes and targets. This led to 169 putative pleiotropic genes significantly associated with at least one of the two conditions. Among these genes, 21 were predicted as potential therapeutic targets of SGLT2 inhibitors in both CKD and HF .Although genetic factors may contribute to the development, progression, and clinical manifestations of T2DM and its complications, they more likely result from complex interactions between genetic, metabolic, and environmental factors. Furthermore, metabolic and environmental factors may alter gene expression levels by tissue-specific epigenetic modifications, such as changes in CpG methylation, posttranslational histone modifications, and changes in expression levels of non-coding RNAs. Periods of high glucose levels shown to lead to tissue-specific epigenetic modifications in various tissues have recently emerged as additional mediators of microvascular complications .The analysis of DNA methylation in proximal kidney tubule cells in a mouse model revealed selective hypomethylation of promotor regions of genes involved in glucose metabolism, including SGLT2 in non-diabetic mice, as compared to gene-specific changes in methylation levels and also hypermethylation of several other metabolic and transporter genes in diabetic mice. These changes in methylation levels were accompanied by histone modification changes as well as changes in gene expression levels. This altered DNA methylation pattern observed in diabetic mice did not reverse under pioglitazone treatment as it led to persistent alterations in mRNA expression levels . This lo1c [A recent meta-analysis of EWAS from five European cohorts identified 76 CpG sites differentially methylated in individuals with T2DM compared with control individuals. Although many of these sites were linked to insulin signaling, lipid homeostasis, and inflammation, the inclusion of the methylation status did not improve the T2DM risk prediction models when compared to the models based on established predictors, such as age, sex, BMI, and HbA1c . The lev1c . As show1c .Several classes of drugs that may target epigenetic changes are being developed with the aim to reverse disease-related epigenetic changes, such as drugs inhibiting DNA methyltransferases, histone acetyl transferases, histone deacetylases, protein methyltransferases, and histone methyltransferases ,97. It hAnother epigenetic mechanism that may be affected by SGLT2 inhibitors is microRNA (miRNA) levels. MiRNAs regulate gene expression at the post-transcriptional level by binding to target mRNAs and silencing their translation. Dysregulation of miRNA expression may trigger the molecular processes of diseases. On the other hand, disease-related processes may lead to dysregulation in miRNA expression. As miRNAs are secreted from the cells into bodily fluids, they are a very promising non-invasive biomarker of disease-related processes. It has been shown in DKD that miRNA expression is dysregulated within the kidney tissue as well as in blood plasma, and methods have rapidly evolved for isolation and analysis of soluble miRNA and miRNA contained within the extracellular vesicles. As membrane antigens and intracellular proteins of extracellular vesicles enable identification of their cells of origin, the analysis of miRNAs in the context of extracellular vesicles, such as small exosomes, may provide even more information on disease pathogenesis than soluble miRNA .In DKD, specific miRNAs have been found to be dysregulated both within the kidney tissue  as well In addition to their potential role as diagnostic and prognostic biomarkers, miRNA may also serve as predictive biomarkers of treatment response. Namely, their specificity and expression levels may also change in response to treatment and are reflected in the circulating miRNA levels. For example, in an open-label study comparing treatment with dapagliflozin or thiazides in 40 T2DM patients, changes occur in expression levels of circulating miRNAs previously described as associated with heart failure, endothelial dysfunction, and kidney damage after 4 weeks of treatment with dapagliflozin, again proving that the protective effects of SGLT2 inhibitors on cardiorenal function may be mediated by epigenetic changes and that specific miRNAs could be used as predictive biomarkers of treatment response .The nephroprotective effects of SGLT2 inhibitors may also be related to their anti-inflammatory effects mediated by decreased circulating levels of inflammatory factors, such as IL-6, TNF receptor-1, matrix metalloproteinase-7, and fibronectin-1, as well as nephroprotective metabolic effects due to reduced ketone production . The invDekkers et al. investigated the effect of dapagliflozin treatment on the levels of markers of glomerular  and tubular damage  and inflammation (urinary MCP-1 and IL-6) in urine samples obtained from 33 T2DM patients during a prospective, randomized, double-blind, placebo-controlled cross-over clinical trial of dapagliflozin versus placebo. They have shown that 6 weeks of treatment with dapagliflozin decreases levels of KIM-1 as a marker of proximal tubular damage as well as levels of inflammatory marker IL-6 in the urine and that the reduction in these markers correlated with the lowering of albuminuria .Heerspink et al. used systems medicine approaches supported by omics technologies to explain molecular mechanisms of disease-related processes and SGLT2 inhibitors treatment response and provided direct evidence regarding how canagliflozin affects the biomarkers related with progression of DKD . Based oAnother study measured the levels of three candidate biomarkers of kidney injury in longitudinally collected plasma samples of T2DM patients obtained at baseline and years 1, 3, and 6 after inclusion in the CANVAS trial. They showed that, over time and in F comparison to placebo, canagliflozin decreased the plasma levels of kidney injury molecule 1 (KIM1) and modestly attenuated the rise of TNFR1 and TNFR2, and that the early reductions in TNFR-1 and TNFR-2 were independently associated with a lower risk of DKD progression .The anti-inflammatory effects of SGLT2 inhibitors were also ascribed to their effects on the increased ketogenesis and increased plasma ketone levels . DespiteAll the described studies indicate that these inflammatory molecules, and, in particular, IL-6, are both key mediators and prospective biomarkers of DKD development.Although the genetic background of T2DM and its complications is firmly confirmed, evidence suggests that there may also be a genetic component to the response to SGLT2 inhibitors. However, the pleiotropic protective effects of SGLT2 inhibitors that extend beyond their glucose-lowering effects of treatment can also be partially ascribed to epigenetic factors and accumulation of the aberrant metabolites that may activate stress response and inflammation and result in a spectrum of clinical phenotypes. It is generally accepted that interactions between genetic, epigenetic, metabolic, and environmental factors may modify the disease risk, the course of these diseases, and treatment outcomes. A better understanding of these molecular mechanisms and their interactions may lead to the discovery of diagnostic, prognostic, and predictive biomarkers that would enable early recognition of individuals at risk for the development of disease or disease-related complications, unfavorable prognosis, or aberrant treatment response and serve as the basis for the application of Predictive, Preventive, Personalized, and Participatory (P3) medicine.


Mortality is high within the first few months of starting chronic dialysis. Pre-ESKD trajectory of kidney function has been shown to be predictive of early death after dialysis initiation. We aim to better understand how two key aspects of pre-dialysis kidney function—an abrupt transition pattern and an episode of dialysis-requiring AKI (AKI-D) leading directly to ESKD—are associated with early mortality after dialysis initiation.2 within 1 year prior to ESKD. AKI-D was identified using inpatient serum creatinine measurements (serum Cr increase by at least 50% from baseline) along with billing codes for inpatient receipt of dialysis for AKI within 30 days prior to the ESKD start date. We used multivariable proportional hazards models to examine the association between patterns of kidney function prior to ESKD and all-cause mortality within 90 days after ESKD.We extracted national data from U.S. Veterans Health Administration cross-linked with the United States Renal Data System (USRDS) to identify patients who initiated hemodialysis during 2009–2013. We defined abrupt transition as having a mean outpatient eGFR ≥ 30 ml/min/1.73mN = 15,484) did not have abrupt transition and did not suffer an episode of AKI-D prior to ESKD (reference group). The remaining groups had abrupt transition, AKI-D, or both. Patients who had an abrupt transition with (N = 503) or without (N = 3611) AKI-D had the highest risk of early mortality after ESKD onset after adjustment for demographics and comorbidities . In contrast, patients who experienced AKI-D without an abrupt transition pattern .Twenty-two thousand eight hundred fifteen patients were identified in the final analytic cohort of Veterans who initiated hemodialysis and entered the USRDS. We defined five patterns of kidney function decline. Most (68%) patients  in this national cohort of Veterans and was strongly associated with higher early mortality after ESKD onset. High death rates within the first few months after starting chronic dialysis is a significant problem in the U.S. and worldwide –4. AccorOlder studies investigating risk factors for mortality early after maintenance dialysis initiation did not have available information about pre-dialysis clinical course –4. In thThese two subgroups of patients presumably overlap partially, since some patients who transition to ESKD abruptly presumably did so because of AKI-D . But preWe used data from the VHA and cross-linked with the USRDS to identify all adult Veterans (age 18 or older) who initiated hemodialysis for ESKD from October 1, 2009 to September 30, 2013. Only incident hemodialysis patients were included. We chose to exclude ESKD patients who initiated peritoneal dialysis or received a kidney transplant, as rates and determinants of death may differ by modality. We excluded patients for whom there were no outpatient serum creatinine measurements within 7–365 days prior to the ESKD start date, as we needed to establish the pre-dialysis mean outpatient eGFR within that time frame. This approach also ensured that the final analytic cohort consisted of patients who were obtaining some clinical care at the VA. Figure Written informed consent was waived by the University of California, San Francisco (UCSF) Institutional Review Board, who waived the informed consent due to the retrospective nature of the study (IRB No. 15–17546). All methods were carried out in accordance with IRB guidelines.“Abrupt transition” is defined as having pre-dialysis mean eGFR of ≥ 30 ml/min/1.73m2 calculated from observed data within the 7–365 day period. We adopted this definition based on prior studies and data suggesting that this cutoff as a predictor of post-dialysis mortality [Pre-dialysis mean outpatient eGFR values (from within 7–365 days prior to ESKD) were derived from the observed serum creatinine measurements taken at a VA facility, excluding measurements during acute care hospitalizations or emergency department visits . “Abruptortality , 15.Hospitalized cases of AKI-D are those that met all of the following criteria: VA acute care hospitalization that lasted at least 24 h, receipt of dialysis during admission  codes 90935, 90937, 90945, 90947 and 90999 –18), andThis definition of AKI based on serum creatinine is the same as that used in the National Institute of Health sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study . HoweverBased on the components described above, the study population could be divided into the following 6 subgroups Fig.  based onN = 15,484No abrupt transition (mean outpatient eGFR < 30 ml/min/1.73m2) and no AKI-D (reference group): N = 2141No abrupt transition (mean outpatient eGFR < 30 ml/min/1.73m2) but experienced AKI-D with ≥ 50% rise in serum creatinine during AKI-D episode: N = 1076No abrupt transition (mean outpatient eGFR < 30 ml/min/1.73m2) but met definition of AKI-D with > 0.3 mg/dL (but < 50%) rise in serum creatinine during AKI-D episode: N = 3611Abrupt transition (mean outpatient eGFR ≥ 30 ml/min/1.73m2) and no AKI-D: N = 503.Abrupt transition (mean outpatient eGFR ≥ 30 ml/min/1.73m2) and experienced AKI-D with ≥ 50% rise in serum creatinine during AKI-D episode: N = 3.Abrupt transition (mean outpatient eGFR ≥ 30 ml/min/1.73m2) and met definition of AKI-D with > 0.3 mg/dL (but < 50%) rise in serum creatinine during AKI-D episode: Owing to the small size of the last group, those three patients were not included in the final analytic cohort Fig. . The finOur primary outcome was all-cause mortality within 90 days of ESKD start date, ascertained using the VA Vital Status Files and data from the USRDS.Demographic characteristics included age, sex, and race/ethnicity. Comorbidities were extracted using ICD-9-CM diagnostic codes up to 4 years prior to the study period and included diabetes, hypertension, coronary disease, peripheral arterial disease, cerebrovascular disease, chronic lung disease, moderate to severe liver disease. Most recent body mass index (BMI) calculated from weight and height, and mean outpatient systolic blood pressure (SBP) within one year prior to dialysis initiation were also extracted from VA data sources.We additionally ascertained the following care practice variables for exploratory analyses. VA care was defined as the number of outpatient visits to any VA facility within the past year prior to ESKD. CKD care was defined as the number of nephrology visits within the four years prior to ESKD. Vascular access was defined according to the first access used for maintenance hemodialysis as listed in the USRDS Medical Evidence files.We used Cox models to determine the association between the pre-ESKD kidney function trajectory patterns of transition to ESKD and mortality within 90 days. We assessed the proportional hazards assumption by testing the Schoenfeld residuals, examining plots of the Schoenfeld residuals over time, examining log–log plots ) versus log of survival time, comparing Kaplan–Meier observed survival curves with predicted curves from the Cox model, and testing for time-dependent covariates. Plots of the Schoenfeld residuals showed no trend over time, and tests of Schoenfeld residuals were not statistically significant. In addition, examination of log–log plots and plots of Kaplan–Meier observed vs predicted survival revealed no evidence of violation of the proportional-hazards assumption, and tests for time-varying covariates were not statistically significant.2) and without a preceding AKI-D event. The final multivariable adjusted model incorporated demographics, comorbidities, BMI, and SBP as covariates.We designated the reference group as those who transitioned to ESKD without abrupt transition .Among the final analytic cohort of 22,815 patients, the median age was 69 years old (interquartile range 62–79); 98% were male, 27% were Black, and 6% were of Hispanic ethnicity. Table N = 15,484 or 68% of the analytic cohort)(Group 1). There were 4,114 patients (18%) who met criteria for abrupt transition; and 2644 patients (12%) who met the definition of AKI-D with ≥ 50% rise in serum creatinine. Only 503 patients (%) had both abrupt transition and AKI-D.The largest subgroup was those who transitioned to ESRD without meeting the criteria for abrupt transition or any definitions of AKI-D  (Table p < 0.001). AKI-D itself without abrupt transition had weaker  association .In final models which controlled for demographics and comorbid conditions Table , similarp < 0.001). In these models, the association of AKI-D only with mortality was mildly attenuated.The strengths of association between abrupt transition and all-cause deaths were attenuated but remained statistically significant in exploratory analysis Table  which fuOf note, individuals classified as meeting the criteria for AKI-D solely on the basis of a ≥ 0.3 mg/dL (but not ≥ 50%) rise in serum creatinine and without abrupt decline of kidney function (Group 3) actually had a lower risk of all-cause mortality within 90 days of ESKD start . This association persisted in fully adjusted & exploratory models , we characterized distinct patterns of kidney function decline leading to incident ESKD and examined the associations between patterns of transition to ESKD with early mortality after dialysis initiation. We evaluated the joint contributions to mortality risk of both the abruptness of kidney function decline, defined as a mean outpatient eGFR ≥ 30 ml/min/1.73mWe showed that 6255 out of 22815 (27%) in the analytic cohort met criteria for having abrupt kidney function decline and/or having experienced AKI-D including ≥ 50% rise in serum creatinine and a new start of dialysis during a hospital admission immediately preceding ESKD. This is consistent with published literature showing that non-linear declines in kidney function are common prior to ESKD , 22, in 2 [Comparing our reported distribution of patterns of transition to ESKD with prior publications is not straightforward in part due to differences in case definition. For example, a prior NIH-funded prospective multicenter cohort study showed that 9% of incident hemodialysis cases had abrupt decline of kidney function, with abrupt decline defined as having a mixed-effects model estimated patient-specific eGFR at 3 months prior to initiation of hemodialysis therapy of ≥ 30mL/min/1.73m2 . A previ2 . However2 . Finally2 . An advaHowever, regardless of the exact definitions for abrupt transition or AKI-D, the consistent observation across this and prior studies has been that patterns of rapid pre-ESKD kidney function trajectory are associated with higher mortality rates after onset of dialysis, compared with reference groups with patterns of slow gradual declines in kidney function and mostly outpatient initiation of chronic dialysis. We chose to focus on mortality within the first three months of dialysis initiation in this paper in part because Healthy People 2020  has as aNone of the prior publications, however, examined what proportion of patients classified with abrupt transition experienced AKI-D. This is in part because subdividing may not have been possible in those studies due to smaller sample size or lack of granular data such as inpatient serum creatinine values and information regarding acute dialysis procedures during hospitalization. We note that, perhaps a bit surprisingly, AKI-D as an immediate proximal precipitant to ESKD only accounted for a minority of those classified as having abrupt transition (only 503 out of 4114 or 12% when AKI was defined as ≥ 50% rise in serum creatinine).Importantly, while both abrupt transition and AKI-D were associated with higher risk of all-cause mortality within 90 days of ESKD start date when controlling for demographics and comorbidities, the associations were stronger for abrupt transition than for AKI-D. The presence or absence of AKI-D did not appear to affect the strength of associations between abrupt transition and all-cause mortality within 90 days of ESKD start  rise in serum creatinine was unexpected (Group 3). The exact reasons for this are unclear, but we suspect this group represented patients with advanced CKD, as they had mean pre-dialysis eGFR of 16 mL/min/1.73mThe strengths of this study include the large sample size, the nationally representative capture of patients receiving care in a single system, and the availability of comprehensive, longitudinal granular laboratory and clinical data. Because of the frequency of laboratory measurements, we did not need to assume linear trajectory of kidney function, which some prior papers had done . We wereN = 463) is still larger than the absolute number of women in other published studies [Limitations of the study include the study population, which was only U.S. Veterans, and therefore the results may not be generalizable to other patient populations. The percentage of women was low (2%), although the absolute number of women  in this vulnerable population.In conclusion


Effective management of comorbid diabetes and hypertension in patients with chronic kidney disease (CKD) is important for optimal outcomes. However, little is known about this relationship from a health plan perspective. The objective of this study was to evaluate the association of effective management of comorbid diabetes and/or hypertension with healthcare resource utilization (HCRU) in patients with chronic kidney disease (CKD).This retrospective cohort study used the Humana Research Database to identify patients with CKD Stage ≥ 3a in 2017. Eligible patients were enrolled in a Medicare Advantage Prescription Drug plan for ≥ 12 months before and after the index date (first observed evidence of CKD). Patients with end-stage renal disease, kidney transplant, or hospice election preindex were excluded. Recommended comorbid disease management included hemoglobin A1c monitoring; adherence to glucose-lowering, cardiovascular, and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker medications; and nephrologist/primary care provider (PCP) visits. HCRU was evaluated for 12 months postindex.The final cohort of 241,628 patients was 55% female and 77% White, with an average age of 75 years. Approximately 90% of patients had Stage 3 CKD. Half had both diabetes and hypertension, and most of the remaining half had hypertension without diabetes. Patients meeting the criteria for good disease management, compared with patients not meeting those criteria, were less likely to experience an inpatient hospitalization, by as much as 40% depending on the criterion and the comorbidities present, or an emergency department visit, by as much as 30%. Total monthly healthcare costs were as much as 17% lower.Management of comorbid diabetes and hypertension in patients with CKD was associated with lower HCRU and costs. Care coordination programs targeting patients with CKD must give careful attention to glucose and blood pressure control.Not applicable. Approximately 37 million people, representing 15% of U.S. adults, have chronic kidney disease (CKD) . AccordiCurrent best-practice guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) organization include recommendations for managing both diabetes and hypertension , 7. It iWhile the positive effects of managing comorbid disease on clinical CKD outcomes are well accepted, less is known regarding how these benefits translate to healthcare resource utilization (HCRU). In 2019, overall Medicare costs for people with CKD were estimated at $87.2 billion, or approximately $24,453 per Medicare beneficiary older than 65 years . An impr2. CKD stage was determined based on the eGFR value, and the diagnoses code in the absence of an eGFR. Eligible patients were enrolled in an MAPD plan for at least 12 months prior to the index date  and at least 12 months following the index date (for measuring outcomes). The index date was the claims date providing the first evidence of CKD, and the observation period for receipt of guideline-recommended care was within 1 year of the index date. We operationalized the five indicators based on internal clinician input, study team experience and guidelines from the Practical Approach to Detection and Management of Chronic Kidney Disease for the Primary Care Clinician [This retrospective cohort study used the Humana Research Database to identify patients 19–89 years of age who were enrolled in a Medicare Advantage Prescription Drug (MAPD) plan and who had claims’ evidence of CKD Stage 3a or greater during the identification period . The Humana Research Database includes patients’ enrollment records, full medical and pharmacy claims, basic demographic information such as age, sex, and geographic region, detailed information on diagnosed medical conditions and procedures performed, and linked outpatient pharmacy records and lab results. Eligible patients had at least two outpatient medical claims with a diagnosis of CKD , at least one inpatient medical claim with a diagnosis of CKD, or at least two serum creatinine laboratory values 90 days apart that translated to an eGFR value less than 60 ml/min/1.73mlinician . For HbAlinician  recommenlinician .Patients with end-stage renal disease diagnosis codes on inpatient or outpatient medical claims or procedure codes indicating receipt of dialysis, recipients of kidney transplant, and patients who elected hospice care were excluded. Figure HCRU was measured by inpatient (IP) hospital admissions and emergency department (ED) visits during the 12 months postindex using facility claims. IP admissions were identified based on bill type code (11) and revenue codes (0190–0219). IP episodes were delineated by admit and discharge cates recorded on the claims. ED visits were identified using revenue codes (045x), place of service codes (23), and Current Procedural Terminology (CPT)/Healthcare Common Procedure Coding System (HCPCS) (CPT/HCPCS) codes indicating procedures performed in the ED setting. For both IP and ED, we created dichotomized outcomes indicating any use during the 12-month follow-up period. For cost outcomes, we calculated total medical costs by summing up allowed costs for all paid medical claims, and we calculated total pharmacy costs by summing up prescription costs for all paid pharmacy claims. Total healthcare costs were calculated by summing up medical and pharamacy costs.CKD stages were based on eGFR values, which were either derived from serum creatinine laboratory results and defined according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation , or werePrimary independent variables were five indicators of good disease management that were assessed in the preindex period: 1) hemoglobin A1c (HbA1c) monitoring, identified by the presence of at least 2 HbA1c laboratory tests among those with evidence of diabetes; 2) adherence to glucose lowering medications, defined as fewer than 60 days off therapy, among those with evidence of diabetes; 3) adherence to cardiovascular therapy, defined as fewer than 60 days off therapy, among those with evidence of hypertension; 4) adherence to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), defined as fewer than 60 days off therapy, among those with evidence of proteinuria according to recorded urine albumin-to-creatinine ratio or a diagnosis code; and 5) clinical care, defined as at least 3 nephrologist visits among those at high renal risk or at least 2 primary care provider (PCP) visits among those at low renal risk. High renal risk was defined by eGFR < 30 and/or albuminuria ≥ 300 mg/g, as recommended in guidance for primary care physicians on when to refer CKD patients to a nephrologist .Baseline demographic and clinical characteristics were summarized for the study sample. Means and standard deviations were reported for continuous variables and counts and percentages for categorical variables. Regression analyses were conducted to examine the association between disease management and outcomes, while controlling for patient demographic characteristics, comorbidities, and CKD stage. Logistic models were used for HCRU outcomes, and generalized linear models with a gamma distribution and log link function were used for cost outcomes. All analyses were conducted separately for the four sub-cohorts: patients with both diabetes and hypertension, diabetes only, hypertension only, or neither. Statistical significance was assessed at the conventional level of 0.05.The final study cohort comprised 241,628 individuals  for the association between good disease management and HCRU outcomes are shown in Table For patients with hypertension only, relevant disease management criteria were significantly associated with a reduction in both IP admissions and ED visits, except for the ACEi/ARB adherence criterion. Statistically significant reductions in the odds of utilization ranged from approximately 10% to 33%, depending on the disease management criterion and outcome measure. Among patients with neither diabetes nor hypertension, consistently significant reductions in utilization were associated with the two provider visit criteria. The other disease management criteria are specific to diabetes and hypertension, and therefore not relevant for this subgroup.The association between good disease management and cost outcomes are shown in Table For patients with both hypertension and diabetes, the patients who met HbA1c monitoring, glucose-lowering therapy, cardiovascular therapy, and nephrologist and PCP provider visit criteria had significantly lower medical PPPM costs, relative to patients not meeting these criteria. The medical cost reductions ranged from 5% for cardiovascular therapy to 24% for HbA1c monitoring. In the diabetes-only subgroup, significant associations with reduced medical PPPM costs were detected for HbA1c monitoring (34% reduction) and glucose-lowering therapy (9% reduction). In the hypertension-only subgroup, the patients who met cardiovascular therapy, nephrologist visit, and PCP visit criteria had significantly reduced medical PPPM. The cost reductions ranged from 5% for cardiovascular therapy to 20% for nephrology visit criteria. Across most groups, pharmacy PPPM costs increased.CKD is common and frequently occurs with comorbid diabetes and hypertension. HbA1c monitoring, adherence to glucose-lowering and CVD medications, and regular physician visits are crucial to the management of CKD among these patients. This study found that meeting best practices of effective disease management in patients with CKD was generally associated with 1-year reductions in HCRU and in total and medical costs. Higher pharmacy costs were typically associated with good disease management. This observation is to be expected since good control of both glucose levels and blood pressure requires adherence to medications. The consistent relative cost reduction across total and medical PPPM categories is expected to more than offset increased pharmacy PPPM costs.Findings from the present study complement prior research showing how the interplay between CKD and comorbid conditions affects utilization and costs. A recent study showed the occurrence of cardiovascular or renal hospitalization to be associated with greater all-cause HCRU and total costs  in patieThe reduction in HCRU and in overall costs observed in this study among patients with well-managed comorbidities may signal a reduction in CKD progression and/or a reduction in clinical conditions that would eventually contribute to CKD progression. The benefits of comorbid disease management could accumulate over time. Study findings not only help demonstrate the validity of current practice guidelines for comorbid disease management in patients with CKD , 7, theyEffective management of patients with CKD who also have diabetes and/or hypertension requires a multifaceted approach that addresses screening, patient education, and comprehensive care. Interventions may target lifestyle change, medication adherence, regular follow-ups and monitoring of glucose level and blood pressure. Practical policies should also aim to reduce patient barriers to guideline-directed care and could include programs to solve for challenges such as transportation and language barriers.Since health plan administrative databases are built primarily for billing and reimbursement purposes, clinical information extracted from these databases may be incomplete or inaccurate. Certain diagnostic information documented in medical records may not be fully captured in submitted claims. As a result, CKD cases, comorbid conditions, and/or outcomes could be undercounted or misclassified. Without access to medical records, it is difficult to gauge the extent of such occurrences. However, since we were comparing outcomes between patient groups and it is unlikely these billing errors or omissions would differ systematically between groups, the impact on our results should not result in systematic bias. Potential misclassification of patients into the low renal risk category due to limited lab data on albuminuria and glomerular filtration rate can occur. Additionally, disease management was operationally defined using process measures  rather than actual clinical outcomes . We utilized the older CKD-EPI equation . given tManagement of diabetes and hypertension in patients with CKD was associated with lower HCRU and costs. This suggests a more coordinated and intentional focus on comorbid conditions for individuals living with CKD may yield measurable benefits to individuals, in the form of fewer hospitalizations and ED visits, and to the system in terms of reduced resource use and costs. Programs to educate patients with CKD on the benefits of managing diabetes and hypertension may support improved outcomes. Policies to support care coordination programs targeting patients with CKD must give careful attention to glucose and blood pressure control and should incentivize clinician adherence to guideline-directed CKD care as well. Future directions for research should investigate how the benefits of comorbid disease management could accumulate over time and which policies provide the most robust and reproducible reductions in HCRU and costs.


Daytime pulse pressure was the strongest indicator of the prevalence of CAD among all analyzed ABPM parameters. ABPM can be used as a valuable tool to identify pancreas recipients who are most susceptible to CAD. We suggest the inclusion of ABPM in pretransplant cardiac screening in type 1 diabetes patients eligible for pancreas transplantation.Having the appropriate tools to identify pancreas recipients most susceptible to coronary artery disease (CAD) is crucial for pretransplant cardiological assessment. The aim of this study is to evaluate the association between blood pressure (BP) indices provided by ambulatory blood pressure monitoring (ABPM) and the prevalence of CAD in pancreas transplant candidates with type 1 diabetes (T1D). This prospective cross-sectional study included adult T1D patients referred for pretransplant cardiological assessment in our center. The study population included 86 participants with a median age of 40 (35–46) years. In multivariate logistic regression analyses, after adjusting for potential confounding factors, higher 24 h BP (systolic BP/diastolic BP/pulse pressure) (OR  =  1.063, 95% CI 1.023–1.105,  Pancreas transplantation is a well-established treatment option for selected patients with diabetes type 1 (T1D) that results in restoring glycemic control, improves the quality of life, and ameliorates diabetic complications .Regardless of the type of surgery, the success of transplantation is at first determined by the perioperative course. In-hospital cardiovascular complications are an important problem among non-surgical complications associated with pancreas transplantation ,4. The mAmbulatory blood pressure monitoring (ABPM) provides a multitude of measurements and seems to be an appropriate tool to solve this problem. The use of ABPM to confirm the diagnosis of hypertension and quantifying the effects of treatment is supported by European and American Guidelines ,12. MoreThe relatively long waiting time for pancreas transplantation provides ample opportunity for intensive screening and adequate interventions to optimize blood pressure control, thus reducing the risk of CAD and subsequent risk of perioperative coronary events. Therefore, it is very important to choose the best CAD indicators from the wide range of measurements provided by ABPM.Therefore, this study aimed to evaluate the association of blood pressure (BP) indices with the prevalence of CAD in pancreas transplant candidates.This prospective cross-sectional study was conducted at the 3rd Department of Internal Medicine and Cardiology, Medical University of Warsaw. The study population included adult T1D patients eligible for pancreas transplantation (PTA/SPK), who were referred for pretransplant cardiological assessment in our center from August 2018 to August 2022. The exclusion criteria included the following: type 2 diabetes; sleep apnea; severe valvular heart disease; heart failure; coronary artery disease; documented arrhythmia; and changes in lipid-lowering and/or in antihypertensive therapy within 3 months before the study entry. The study protocol was conducted following the Declaration of Helsinki and was approved by the local Bioethics Committee at the Medical University of Warsaw, Poland (no. KB/115/2018). All participants signed an informed consent form to participate in the study.The following demographic and clinical variables were collected: age; sex; diabetes duration; renal replacement therapy; type of planned transplantation procedure (PTA/SPK); smoking status; hypertension; dyslipidemia; and the use of antihypertensive and lipid-lowering drugs. Hypertension was defined as systolic blood pressure (SBP) > 140 mmHg or diastolic blood pressure (DBP) > 90 mmHg and/or a patient on antihypertensive therapy before admission. Dyslipidemia was diagnosed if at least one of the following values was met: total cholesterol (TC) ≥ 5.0 mmol/L; low-density lipoprotein-cholesterol (LDL-C) ≥ 3.0 mmol/L; triglycerides (TG) ≥ 1.7 mmol/L; and if a patient was on lipid-lowering therapy. Current smoking was defined as active cigarette smoking in the last 5 years before inclusion in the study.2.All participants were weighed after overnight fasting and dialysis patients were weighed on their non-dialysis day. Body mass index (BMI) was calculated as weight [kg] divided by the square of height [m]. Obesity was defined as a BMI ≥ 30 kg/mBlood samples were collected after overnight fasting. The concentrations of glycated hemoglobin (HbA1c), creatinine, TC, high-density lipoprotein-cholesterol (HDL-C), and TG were measured using a commercially available analyzer . The concentration of LDL-C was calculated according to the Friedewald formula .AMBP was recorded in all participants using the validated oscillometric device  in agreement with the current guidelines of the European Society of Hypertension (ESH) . Measure2)—were directly referred for coronary angiography. The other patients underwent stress tests, which included an exercise stress test on a treadmill (EST) or pharmacologic stress test. EST was performed in patients with a normal resting electrocardiogram who were able to exercise adequately. The patients exercised according to the standard Bruce protocol, which consists of 3 min stages with increased speed and incline of the treadmill at each stage. Patients with physical limitations or inconclusive results of EST were subjected to a pharmacologic stress test using dipyridamole 99 mTc-sestamibi single-photon emission computed tomography (SPECT). Positive results on stress tests uniformly led to invasive coronary angiography. Coronary angiography was used instead of coronary CT angiography due to patients’ risk profile, high likelihood of extensive coronary calcification (due to CKD), local expertise, and availability. Coronary angiography was performed using a Philips Allura Xper DF20 X-ray system with standard diagnostic catheters through radial access. The obstructive CAD was defined as at least one ≥50% lesion in an artery with ≥2 mm caliber.CAD was evaluated based on stress tests and invasive coronary angiography. Patients with a high clinical likelihood of CAD—with long-standing diabetes (T1D duration ≥ 20 years) and/or severe chronic kidney disease . The Shapiro–Wilk test was used to test the normality of the data distribution. For parameters without normal distributions, statistical analyses were based on non-parametric tests. The Mann–Whitney U test was used to compare numerical variables between two groups, and the Fisher’s exact test or chi-squared test was used to examine the relationship between categorical variables. The correlation between ABPM parameters and CAD and between ABPM parameters and potential predictors of CAD  was checked using Spearman’s correlation coefficient (r). The following classification of the correlation strength was used: 0.0 ≤ |r| ≤ 0.2, no correlation; 0.2 ≤ |r| ≤ 0.4, low correlation; 0.4 ≤ |r| ≤ 0.7, moderate correlation; 0.7 ≤ |r| ≤ 0.9, high correlation; 0.9 ≤ |r| ≤ 1.0, very high correlation.p-value < 0.05 was considered significant.A multivariate logistic regression analysis was used to test the combined relationship between the presence/absence of CAD and selected ABPM parameters adjusted for confounding factors, including age, hypertension, smoking, TG, statins use, and hemodialysis. Each model consists of only one of the parameters from ABPM  and the same set of potential confounding factors. The multivariate model used the backward, stepwise elimination method, starting with a model including all the variables. The results were presented as odds ratio (OR) with a 95% confidence interval (CI). Statistical analyses were performed using Statistica version 13.3 . For all statistical analyses, a The study population included 89 patients, but 3 of them were excluded from further analysis because the number of useless ABPM readings exceeded 70%. The statistically analyzed study population included 86 participants with a median age of 40 (35–46) years, 41 (47.7%) of whom were men. The baseline characteristics of the participants are illustrated in n = 70; 81.4%) had long-standing diabetes (duration > 20 years). Depending on kidney function, patients qualified for PTA  or SPK . The majority of SPK candidates were on HD , whereas nine patients (14.7% out of SPK) were qualified for preemptive transplantation. The prevalence of classical cardiovascular risk factors was very high, and hypertension was the most common CRF in our cohort . The majority of hypertensive patients reported the use of antihypertensive drugs  and the majority of dyslipidemic patients reported the use of statins .The median duration of T1D was 26 (22–31) years, and most of the participants  were referred directly for coronary angiography, 86.4% of them (n = 70) due to long-standing diabetes (T1D duration ≥ 20 years) and 13.6% of them (n = 11) due to severe chronic kidney disease (eGFR < 30 mL/min/1.73 m2). The other patients (n = 5) underwent stress tests: two patients had EST, two patients had SPECT, and one patient had both EST and SPECT. Out of all the stress tests, three were reported as negative and two were reported as positive. Positive stress tests led to invasive coronary angiography.Most participants (n = 26). According to the Heart Team decision, one person (3.8% out of patients with CAD) was disqualified from pancreas transplantation due to diffuse coronary lesions unsuitable for any method of revascularization; four patients (15.4% out of patients with CAD) qualified for CABG; and 8 (30.8% out of patients with CAD) underwent PCI. Half of the patients with CAD (n = 13) qualified for optimal medical therapy and were approved for pancreas transplantation. Patients subjected to revascularization will be reevaluated as candidates for pancreas transplantation after invasive treatment of CAD.Finally, coronary angiography was performed in 83 patients (96.5% of the entire cohort). CAD was diagnosed in 30.2% of participants (The differences in cardiovascular risk factors between patients with and without CAD are shown in n = 46) and as much as in 73% of patients with CAD (n = 19). The 24 h SBPL was significantly higher in patients with CAD than in patients without CAD (53.5% (31–91) vs. 33% (12–51), p = 0.002). There were no significant differences in 24 h DBPL between the analyzed groups (The median 24 h BP was 131.5 mmHg (124–147) and exceeds the therapeutic goal (24 h BP < 130/80 mmHg) in 53.5% of the entire cohort  and the prevalence of CAD in the study group .Spearman’s correlation analysis was used for testing the correlation between selected ABPM parameters and CAD. Based on Spearman’s correlation matrices, we found a significant, weak correlation between both 24 h SBP and 24 h SBPL and CAD. There was no significant correlation between 24 h DBP and between 24 h DBPL . In addip = 0.002 and OR = 1.075, 95% CI 1.003–1.153, p = 0.042 and OR = 1.091, 95 CI 1.037–1.147, p= 0.001, respectively), and higher daytime BP  were significantly and independently associated with the prevalence of CAD. Daytime PP was the strongest indicator of the prevalence of CAD among all analyzed ABPM parameters. When daytime PP increased by 1 mmHg, the odds of having CAD increased 1.11 times. No significant association was found between night-time BP  and the prevalence of CAD , higher 24 h BP   were significantly associated with the higher prevalence of CAD. The associations remained significant after adjusting for well-known cardiovascular risk factors, including hemodialysis. Daytime PP was the strongest indicator of the prevalence of CAD in our cohort. No significant association was found between night-time BP  and the prevalence of CAD. Moreover, there was no significant correlation between CAD and BP dipping status. In addition, we identified that BP values exceeded the therapeutic goal in the majority of the enrolled patients, even though they were on antihypertensive therapy.CAD was found in one third of the study population. The prevalence of CAD in our population was relatively low, although the study group was exposed to a very high cardiovascular risk. Our finding is opposite to that of St Michel D. et al., who detected discrete evidence of CAD in 71.7% of T1D candidates for SPKT subjected to coronary angiography. However, when considering all their T1D patients qualified for SPKT, CAD was diagnosed in 47.5% (28 out of 59 subjects) . SimilarIn our study, there was a similar prevalence of CAD in women and men. Our results are in line with other researchers who have found that diabetic women lose their female protection against cardiovascular disease ,23,24. OIn addition, we demonstrated that in more than half of the entire cohort, BP values exceeded the therapeutic goal, even though the patients were undergoing antihypertensive therapy. The number of people with insufficient BP control among patients with CAD was much higher and exceeded 70%. These results demonstrate that most patients were treated unsuccessfully, likely due to the lack of a valuable monitoring tool.Our analysis has shown that higher 24 h and daytime median BP values  were significantly associated with the higher prevalence of CAD. Moreover, we confirmed that each of the above BP parameters was an independent predictor of the increased probability of the prevalence of CAD after adjusting for potential confounding factors. Our results demonstrate that strict control of BP values is crucial in this population. The most impressive result was that daytime PP was the strongest independent predictor of the prevalence of CAD in our cohort. PP is a surrogate indicator of arterial stiffness ,31. ArteWe did not find any significant associations between night-time BP and the prevalence of CAD. Furthermore, there were no significant differences between nocturnal dipping status and the prevalence of CAD, either. Our findings are in contrast to some studies showing that the non-dipper pattern is associated with a higher cardiovascular risk ,37,38. HPancreas transplantation is a high-risk surgery because of the risk of adverse coronary events. Vigorous cardiological pretransplant assessment is a key to the identification of those particularly vulnerable to cardiovascular complications. The average waiting time for a pancreas transplantation (PTA/SPK) is one to two years . Thus, tOur study has some limitations; first is the small sample size. However, the study group is fully representative because of the low number of patients referred for pancreas transplantation in our country. The second limitation of our study is its cross-sectional nature, which limits the ability to establish causal relationships. Third, the definition of daytime and night-time were determined according to clock time, regardless of the actual activity of the patient. However, Dimsdale et al. demonstrated adequate reliability between the BP results regardless of the method used to determine night-time . AnotherHypertension is a very important cardiovascular risk factor in candidates for pancreas transplantation. ABPM can be used as a valuable screening tool to identify patients who are most susceptible to CAD. We suggest the inclusion of ABPM in pretransplant cardiac screening in T1D patients eligible for pancreas transplantation.


Scientific evidence on patients with multimorbid type 2 asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a united airways disease (UAD) perspective remains scarce, despite the frequent coexistence of these entities. We aimed to generate expert consensus-based recommendations for the management of UAD patients.Using a two-round Delphi method, Spanish expert allergists, pulmonologists and otolaryngologists expressed their agreement on 32 statements (52 items) on a 9-point Likert scale, classified as appropriate (median 7–9), uncertain (4–6) or inappropriate (1–3). Consensus was considered when at least two-thirds of the panel scored within the range containing the median.A panel of 30 experts reached consensus on the appropriateness of 43 out of the 52 (82.7%) items. The usefulness of certain biomarkers  in the identification and follow-up of type 2 inflammation, and assessment of the response to biologics, were agreed. Some of these biomarkers were also associated with disease severity and/or recurrence after endoscopic sinus surgery (ESS). Consensus was achieved on treatment strategies related to the prescription of anti-IL-4/IL-13 or anti-IgE agents, concomitant treatment with systemic corticosteroids, and combining or switching to biologics with a different mechanism of action, considering a number of UAD clinical scenarios.We provide expert-based recommendations to assist in clinical decision-making for the management of patients with multimorbid type 2 asthma and CRSwNP. Specific clinical trials and real-world studies focusing on the single-entity UAD are required to address controversial items.The online version contains supplementary material available at 10.1186/s13223-023-00780-9. The concept of united airways disease (UAD) embodies a comprehensive approach to the management of upper and lower respiratory diseases, which are anatomically and immunologically related , 2. SeveType 2 (T2) inflammation is the most common endotype in both asthma and CRSwNP Caucasian populations , 10, andCurrently, combined therapeutic strategies for severe asthma and CRSwNP are mainly focused on reducing systemic corticosteroids (SCS) in maintenance and bursts, thereby minimizing asthma exacerbations and worsening of CRSwNP , 13, andOverall, scientific evidence on the management of multimorbid patients is scarce because clinical trials and real-world studies mostly evaluate the treatment of asthma or CRSwNP as single entities, or considering each a comorbid condition, rather than UAD. As such, several studies reporting data on biomarkers –22, biolThis study was designed based on a modified Delphi method and included a Spanish multidisciplinary board of allergists, pulmonologists, and ENT specialists with clinical expertise in the management of asthma and CRSwNP. A questionnaire was first developed by a scientific committee and participants were then asked to respond to several statements in a two-round online Delphi survey .The scientific committee consisted of 3 allergists , 3 pulmonologists , and 3 ENT specialists  with extensive expertise in the management of asthma, CRSwNP and their multimorbidity. The committee members were responsible for developing the Delphi questionnaire, reviewing final outcomes, and interpreting the results. An expert panel of 30 members was selected by the scientific committee from the Spanish Society of Allergy and Clinical Immunology (SEAIC) (n = 10), the Spanish Society of Otorhinolaryngology and Head and Neck Surgery (SEORL-CCC) (n = 10), and the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) (n = 10). Members were contacted by email to participate as panelists in the Delphi survey. Inclusion criteria were: (1) working in clinical practice within the Spanish National Health System, in public or private centers, and (2) at least five years of expertise in the management of patients with asthma and CRSwNP. Participants were identified across several Spanish geographical regions to guarantee appropriate representativeness. Due to a lack of response, two additional experts from SEAIC and one from SEPAR were contacted.post hoc studies, clinical practice guidelines, and observational studies reporting data on the management of T2 asthma and CRSwNP were included. In total, 32 publications were selected and assessed using the Critical Appraisal Skills Programme checklists [The Delphi questionnaire was drafted after a previously published systematic review that summarized recent evidence on the management of UAD (PROSPERO CRD42021262844) . Brieflyecklists .Based on the studies retrieved and clinicians’ expertise, controversial issues and unmet needs were identified by the scientific committee. A preliminary draft of the questionnaire was developed and subsequently discussed in a virtual meeting. The scientific committee drew conclusions and suggested several recommendations to formulate the statements that could be proposed to the panel. Finally, the Delphi questionnaire was prepared with 32 statements (52 items) that were grouped into three sections: (1) identification of phenotypes (8 statements); (2) treatment (16 statements); and (3) follow-up (8 statements).Consensus was based on the RAND Healthcare Corporation and University of California at Los Angeles (RAND/UCLA) Appropriateness Method . In the In total, 30 out of the 33 experts participated in both consultation rounds of the Delphi questionnaire (response rate 90.9%) over a two-month period. Participants had a median (range) of 20 10–35) years of medical expertise and were from nine different Autonomous Communities in Spain  Table . While aConsensus was achieved on the association of some biomarkers with increased severity in patients with T2 asthma and CRSwNP, such as elevated FeNO (M: 7) and peripheral blood (M: 8) and tissue eosinophil count (M: 9). In contrast, the association of elevated total serum IgE (M: 8) and positive specific IgE (skin or blood) (M: 5) with severity was overall controversial for all specialties. Experts agreed on the association of tissue eosinophil count with recurrence after ESS (M: 8), whereas controversy was observed for peripheral blood eosinophil count for allergists and ENT specialists. The panel strongly agreed that loss of smell should be assessed in patients with severe asthma and/or CRSwNP (M: 9).Most experts agreed on the need to evaluate a combination of parameters, including clinical variables and biomarkers, to predict treatment response in patients with severe T2 asthma and CRSwNP (M: 9) . Regarding the need for short courses of SCS in patients receiving biologics who have not achieved disease control, the experts indicated that it should not be considered as treatment failure if response criteria for the biologics are met (M: 7). The panel agreed that the combination of two biologics with different mechanisms of action may be necessary in patients with UAD who have not achieved symptom control after medical-surgical treatment and use of a biologic (M: 8). However, they also stated that combining biologics is not advisable due to cost-effectiveness and/or lack of safety evidence (M: 8). Accordingly, most experts recommended switching to biologics with a different mechanism of action, or performing ESS if applicable, in UAD patients who do not respond to biologics, even when an improvement in the variables associated with asthma or CRSwNP is observed (M: 7–9). The experts also recommended extending maintenance treatment for at least 6 months before considering withdrawal or switching in UAD patients who show an initial good response (M: 8.5).The panel strongly agreed on biomarkers associated with T2 inflammation that are useful for the follow-up of patients with severe asthma and CRSwNP treated with biologics, including peripheral blood and tissue eosinophil count (M: 8), and FeNO (M: 8), whereas controversy was observed for serum total IgE (M: 7.5) and specific IgE (M: 5) Table . AllergiGiven the paucity of scientific evidence supporting certain therapeutic strategies for UAD in clinical practice, a multidisciplinary Delphi survey was conducted to elicit expert-based recommendations. To the best of our knowledge, this is the first Delphi study on the management of patients with multimorbid T2 asthma and CRSwNP from a UAD perspective. Outcomes of the questionnaire revealed an overall 83% rate of consensus among allergists, pulmonologists, and ENT specialists, most of whom agreed on the appropriateness of the proposed items. Among these, experts valued the usefulness of several biomarkers to assess and monitor T2 inflammation, as well as their association with disease severity, response to biologics, or recurrence after ESS. Treatment recommendations were made on the prescription of biologics, concomitant treatment with SCS, and combining or switching to other biologics with a different mechanism of action, considering a number of UAD clinical scenarios.The identification of phenotypes and underlying endotypes is currently the best approach to define UAD and predict the patient’s prognosis , 5, 33. The association of disease severity with elevated serum total IgE in UAD patients was controversial, likely due to a lack of scientific evidence. In fact, a study performed in patients with allergic asthma showed high and variable IgE levels . InteresAlthough the association of peripheral blood eosinophil count and recurrence after ESS was overall controversial, allergists considered this statement uncertain while pulmonologists and ENT specialists considered it appropriate. In this regard, a recent study has shown that blood eosinophil count combined with asthma history could predict CRSwNP recurrence . MoreoveGiven the common pathological characteristics underlying both asthma and CRSwNP, as well as the increased disease burden in multimorbid patients, integral treatment of T2 inflammation in UAD is warranted , 33. WhiThe use of biologics before ESS, in the context of severe uncontrolled asthma and CRSwNP, was uncertain and controversial due to the scant evidence . Indeed,Experts agreed on the appropriateness of combining two biologics in UAD patients who have not achieved disease control. However, combination of these agents remains controversial, with very limited evidence and only in asthma patients . Since tFor the follow-up of UAD patients receiving biologics, experts agreed on the appropriateness of T2 biomarkers such as peripheral blood and tissue eosinophil count, in line with those established for the indication of the treatment , 13, 50.FeNO has been associated with asthma exacerbations and lung function . In patiAmong the clinical markers that the expert panel considered appropriate to determine a lack of response to ESS, anosmia is not currently used in clinical practice. Accordingly, although there was overall agreement, differences were observed among specialties. Recent studies have demonstrated poor mid- to long-term efficacy of ESS in the loss of smell, apart from the effect of initial surgeries , 53. On This study is subject to certain limitations, which are mainly related to the Delphi methodology. To minimize imposed preconceptions and ensure impartiality in the design of the questionnaire, all statements were thoroughly reviewed and subsequently agreed upon by the scientific committee members. It is worth noting that the experts’ evaluation may be affected by personal interpretation of the statements and/or their own clinical expertise. Considering that there might be a potential bias in the selection of the expert panel, a large number of specialists from different Autonomous Communities in Spain were included.In summary, this Delphi survey provides expert-based recommendations that may assist healthcare professionals involved in the management of multimorbid T2 asthma and CRSwNP patients, and guide clinical decision-making from the UAD perspective. Although the level of consensus among specialists constituting the expert panel was overall high, some controversies came to light. Therefore, we emphasize the need for specific clinical trials and real-world studies considering the single-entity UAD to further support consensus recommendations, but also to address the unmet needs identified herein. Future research will help to ascertain the best management algorithm and therapeutic strategies according to the patient profile and history, and eventually enable evidence-based implementation of clinical practice guidelines.Additional file 1: Table S1. Characteristics of the study expert participants.Table S2. Data on controversial items in the Delphi survey by specialty.


Remote ischemic conditioning (RIC) is delivered by a blood pressure cuff over the limb, raising pressure 50 mmHg above the systolic blood pressure, to a maximum of 200 mmHg. The cuff is inflated for five minutes and then deflated for five minutes in a sequential ischemia-reperfusion cycle 4–5 times per session. Elevated pressure in the limb may be associated with discomfort and consequently reduced compliance. Continuous assessment of relative blood concentration and oxygenation with a tissue reflectance spectroscopy  placed over the forearm during the RIC sessions of the arm will allow us to observe the effect of inflation and deflation of the pressure cuff. We hypothesize, in patients with acute ischemic stroke (AIS) and small vessel disease, RIC delivered together with a tissue reflectance sensor will be feasible.The study is a prospective, single-center, randomized control trial testing the feasibility of the device. Patients with AIS within 7 days from symptoms onset; who also have small vessel disease will be randomized 2:1 to intervention or sham control arms. All patients randomized to the intervention arm will receive 5 cycles of ischemia/reperfusion in the non-paralyzed upper limb with a tissue reflectance sensor and patients in the sham control arm will receive pressure by keeping the cuff pressure at 30 mmHg for 5 minutes. A total of 51 patients will be randomized, 17 in the sham control arm and 34 in the intervention arm. The primary outcome measure will be the feasibility of RIC delivered for 7 days or at the time of discharge. The secondary device-related outcome measures are fidelity of RIC delivery and the completion rate of intervention. The secondary clinical outcome includes a modified Rankin scale, recurrent stroke and cognitive assessment at 90 days.RIC delivery together with a tissue reflectance sensor will allow insight into the blood concentration and blood oxygenation changes in the skin. This will allow individualized delivery of the RIC and improve compliance.NCT05408130, June 7, 2022.ClinicalTrials.gov Identifier:  Cerebral small vessel disease (cSVD) is common and characterized by the presence of white matter lesions, microbleeds, prominent perivascular spaces, lacunar infarcts and intracerebral hemorrhages. The presence of cSVD is associated with an increased risk of stroke recurrence, worse functional outcome and persistent cognitive impairment following an acute ischemic stroke . CurrentRemote Ischemic Conditioning (RIC) is the technique of transient focal ischemia and reperfusion to a vascular bed, tissue, or organ. This may increase tissue tolerance to ischemia and prevent damage due to the ensuing cascade . In a caCurrent RIC standard practice is to deliver ischemia by increasing the pressure in the arm BP cuff by 50 mmHg above the systolic blood pressure (to a maximum of 200 mmHg). These high pressures may be associated with discomfort, consequently reducing the patient’s compliance with the intervention . The reqOur group has developed a skin tissue reflectance spectroscopy device for RIC delivery monitoring. In this clinical trial, we will assess the device’s feasibility. We hypothesize, in patients with ischemic stroke and small vessel disease, RIC delivered together with a tissue reflectance sensor will be feasible.A prolonged occlusion arm pressure cuff was developed using an off-the-shelf Blood Pressure(BP) monitor, and a solenoid-actuated valve was added that allows pressure feedback to sustained pressure for 5 min. This added component enabled the blood pressure machine provide two modes:BP mode which assesses the systolic/diastolic BP and Ischemic; conditioning mode which sustains pressure for 5 min followed by deflation for 5 cycles. The optical sensor comprised a 3-wavelength high output LED (Marktech MTMD6894T38) operating at 670, 810, 950nm, a regulated LED driver circuit and a microcontroller  that controlled the sequence for illuminating the LEDs and processed the relative amplitude of the backscattered light from the skin that was detected with an array of OPT101 (Text Instruments) photodetectors.The LED is placed in the centre and is surrounded by the photodetectors. The sensor estimated the relative blood concentration and oxygenation in real-time during RIC therapy inflation and deflation. It wirelessly transmitted the measurements to a laptop computer that stored the readings and provided the clinician with a dashboard to monitor the readings throughout the treatment cycle. The indices of blood oxygenation (2 measures) and concentration were calculated using the following formulas:By sampling the LEDs quickly and sampling at over 5 min complete measurements every second it is also possible to monitor the pulse rate as the blood concentration increases up to systole and decreases to diastole. There is a characteristic decay in the blood oxygenation during ischemia and then a rapid recovery with a small overshoot above baseline, and then a gradual return to baseline. These parameters can be used to characterize the difference in individual patients’ tissue responses.The study is designed as a randomized control, single-blinded (patient), single-center, parallel-group, 1:2 randomization to sham control arm vs intervention arm, phase 2 clinical trial to assess the feasibility . The stuAcute stroke patients within 48 hours from symptom onset will be screened. Adult patients aged 18 years or more with ischemic stroke (anterior and posterior circulation involvement) with or without neurological deficit, with evidence of infarct and small vessel disease on either computed tomography (CT) of the head or magnetic resonance imaging (MRI) of the brain, will be included after written informed consent is obtained from the patient or substitute decision maker. Infarct will be defined as new hypodensity in the CT head or hyperintensity in diffusion-weighted imaging with corresponding hypo-intensity in the apparent diffusion coefficient imaging. Small vessel disease will be defined as the presence of periventricular hyperintensities/hypodensities, deep white matter hyperintensities/hypodensities, microbleeds on MRI, new or old lacunar infarcts and Virchow Robin spaces in either CT or MRI. Patients with a pre-stroke functional disability as assessed by a modified Rankin scale of 2 or more, and a severe neurological deficit as assessed by the National Institute of Health Stroke Scale of 15 or more will be excluded. Patients receiving oral or parenteral anticoagulation therapy will be excluded. Patients with injury to the arm/forearm or any other musculoskeletal disability/pain and dermatological conditions affecting the application of tissue perfusion sensor and RIC pressure cuff will be excluded. Patients who are receiving ongoing treatment for active malignancy with expected survival <6 months, who have hypertensive urgency and emergency, ongoing systemic infection and hemodynamically instability will be excluded. Pregnant and lactating women will be excluded as the effect of RIC on the fetus is not known.All patients randomized to the intervention arm will receive 5 cycles of ischemia/reperfusion in the non-paralyzed upper limb with the use of an optical feedback sensor to keep the blood pressure target 30–50 mmHg above the systolic BP to a maximum of 200 mmHg. Each cycle will last for 5 minutes of ischemia (by inflating the blood pressure cuff above systolic BP) followed by 5 minutes of reperfusion (deflation of the cuff). If there is no upper limb paralysis, the non-dominant arm will be used. Patients will receive RIC therapy once daily for a period of 7 days or during their hospital stay whichever is shorter. The subjects in the sham group will receive a similar type and duration of pressure sensation by keeping the pressure at 30 mmHg in the non-paralyzed arm or if no upper limb paralysis non-dominant arm. All RIC therapy and sham control sessions will be monitored by the study personnel. The therapy sessions will be delivered at the bedside in the stroke unit .During the RIC therapy, if the patient develops pain and wants to stop the procedure the session will be terminated immediately and documented as protocol deviation. The patient would be approached again the next day for the therapy session if they agree the therapy will be continued. However, if they disagree or the pain re-occurs it will be considered as termination of the trial. In situations of worsening of patient’s clinical conditioning which require the patient to be moved to a high care setting the RIC therapy will be temporarily stopped. The RIC therapy session will resume once the patient is clinically stable.All patients in the sham and intervention arm will receive standard of care management for ischemic stroke as per the Canadian Stroke Best Practices Guidelines .The primary outcome measure is the safety and feasibility of RIC delivered during the first 7 days or till discharge. Safety outcome measures will include assessing the level of comfort with the Likert scale after each therapy session. The Likert scale is a psychometric scale used for outcome assessment. The Likert scale will be used to measure comfort post-procedure and will be divided into 5 levels very comfortable, comfortable, neither comfortable nor uncomfortable, uncomfortable and very uncomfortable . PersistA 1:2 block randomization list was generated using sealedenvelope.com and kept with a blinded study investigator. Participants will be randomly assigned to either a sham or intervention group according to the list. The study investigator enrolling the patient will call the blinded study investigator to get a randomization group.The patient will be blinded to the therapy arm. Assessment regarding comfort using the Likert scale and persistent safety concerns lasting for >10 minutes will be assessed by the study investigator delivering the RIC therapy session. The mRS, cognitive assessment and recurrent stroke at 90 days will be assessed by a blinded investigator to the therapy arm. Due to the nature of the intervention, the investigator delivering therapy cannot be blinded to allocation.Patient demographic, clinical, laboratory, imaging and medication details will be abstracted on an electronic case record form. Case record form (CRF) at baseline will include premorbid functional status, risk factor profile, vital signs, the arterial territory of qualifying stroke, revascularization therapy and imaging findings including the severity of small vessel diseases. We will assess BP prior to each intervention session. Patient comfort, measured by a Likert scale will be recorded after each cycle. Persistent safety concerns lasting for >10 minutes after completion of RIC will also be recorded. Follow-up in 3 months will be done through a telephone call.We will enroll a total of 51 (17 in Sham Control and 34 in the Intervention arm) patients over a 9-month period. The stroke risk factors will be reported as percentages. NIHSS will be reported as median with interquartile range. The Likert scale will be used to measure the comfort post-procedure, the Likert scale is 5 points ordinal scale to which the patient agrees or disagree with the procedure. Each group will be divided into two groups who achieved good feasibility Likert scale <3 and not feasible Likert scale >2. They will be compared with the Chi-Square test or Fischer Exact test. The safety endpoint and completion rate will be described as percentages. The 1:2 randomization will allow better detection of feasibility and safety concerns. The median (IQR) blood concentration and median (IQR) oxygen concentration (both frequencies 768 and 868) change for each cycle will be assessed for all sessions . The medRIC-device therapy is promising, non-invasive and may be cost-effective in acute ischemic stroke. However real-time monitoring may allow insights into the delivery of RIC. A novel tissue reflectance sensor coupled with RIC therapy is being tested in this clinical trial. The changes in blood concentration and blood oxygenation during the delivery of RIC therapy will provide data on the physiological changes occurring in the skin capillaries. This will allow individualized delivery of the RIC and improve compliance.S1 Checklist(DOC)Click here for additional data file.S1 File(PDF)Click here for additional data file. 11 Apr 2023Assessment of Remote Ischemic Conditioning delivery with Optical Sensor in Acute Ischemic Stroke: Randomised Clinical Trial Protocol.PONE-D-23-07917Dear Dr. Kate,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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