IL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.

The high mortality rates of acute lung injury and acute respiratory distress syndrome challenge the field to identify biomarkers and factors that can be exploited for therapeutic approaches. IL-22 is a cytokine that has antibacterial and reparative properties in the lung. However, it also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A+ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1+ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1ß, IL-6, and transforming growth factor-ß1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.

Philadelphia Latine Immigrant Birthing People's Perspectives on Mitigating the Chilling Effect on Prenatal Care Utilization.

RESEARCH DESIGN: Community-engaged qualitative study using inductive thematic analysis of semistructured interviews. OBJECTIVE: To understand Latine immigrants' recent prenatal care experiences and develop community-informed strategies to mitigate policy-related chilling effects on prenatal care utilization. BACKGROUND: Decreased health care utilization among immigrants due to punitive immigration policies (ie, the "chilling effect") has been well-documented among Latine birthing people both pre and postnatally. PATIENTS AND METHODS: Currently or recently pregnant immigrant Latine people in greater Philadelphia were recruited from an obstetric clinic, 2 pediatric primary care clinics, and 2 community-based organization client pools. Thematic saturation was achieved with 24 people. Participants' pregnancy narratives and their perspectives on how health care providers and systems could make prenatal care feel safer and more comfortable for immigrants. RESULTS: Participants' recommendations for mitigating the chilling effect during the prenatal period included training prenatal health care providers to sensitively initiate discussions about immigrants' rights and reaffirm confidentiality around immigration status. Participants suggested that health care systems should expand sources of information for pregnant immigrants, either by partnering with community organizations to disseminate information or by increasing access to trusted individuals knowledgeable about immigrants' rights to health care. Participants also suggested training non-medical office staff in the use of interpreters. CONCLUSION: Immigrant Latine pregnant and birthing people in greater Philadelphia described ongoing fear and confusion regarding the utilization of prenatal care, as well as experiences of discrimination. Participants' suggestions for mitigating immigration-related chilling effects can be translated into potential policy and programmatic interventions which could be implemented locally and evaluated for broader applicability.

Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

Unexpected Diversity of Pseudomonads Associated with Bacterial Leaf Spot of Cucurbits in the Southeastern United States.

Bacterial leaf spot of cucurbits (BLS) is an emerging disease in the southeastern United States that is capable of causing widespread outbreaks under conducive conditions. Historically attributed solely to the bacterium Pseudomonas syringae pv. lachrymans, recent studies have identified additional P. syringae pathovars as causal agents of the disease. To further investigate the identity and diversity of P. syringae strains associated with BLS in the southeastern United States, 47 bacterial isolates were recovered from symptomatic cucurbits from Florida, Alabama, and Georgia. Strains were characterized using the LOPAT testing scheme, fluorescence, and pathogenicity to watermelon and squash seedlings. Thirty-eight fluorescent isolates underwent whole-genome sequencing and were further characterized with 16S rRNA, four gene multilocus sequence analysis (MLSA) phylogeny, and average nucleotide identity analysis. Thirty-four isolates were identified as members of the P. syringae species complex, including P. syringae sensu stricto (12), P. alliivorans (12), P. capsici (nine), and P. viridiflava (one). An additional four isolates were found to belong to the Pseudomonas genus outside of the syringae species complex, though they did not share 95% or greater average nucleotide identity to any validly published species and are believed to belong to three novel Pseudomonas species. These results reveal an unpredicted level of diversity of Pseudomonas strains associated with BLS in the region and show the benefits of whole-genome sequencing for strain identification. Identification of P. capsici, which is capable of causing disease at higher temperatures than P. syringae, as a causal agent of BLS may also affect management strategies in the future.

High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet.

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 wk to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and ANG II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 wk in females fed either an NFD or HFD. Significant sex differences were found after 28 wk of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and ANG II. T2DM in males was accompanied by nondipping hypertension, carotid artery stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and systolic blood pressure. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.NEW & NOTEWORTHY High-fat diet (HFD) for 28 wk leads to type 2 diabetes mellitus (T2DM) phenotype, concomitant with increased plasma soluble prorenin receptor (sPRR), nondipping blood pressure, and vascular stiffness in male mice. HFD-fed female mice exhibiting a preserved cardiometabolic phenotype until ovariectomy revealed increased plasma sPRR and blood pressure. Plasma sPRR may indicate the status of systemic renin-angiotensin-aldosterone system (RAAS) activation and the onset of vascular complications during T2DM in a sex-dependent manner.

Impact of COVID-19 on Infants followed after Discharge from the Neonatal Intensive Care Unit Using a Telemedicine Model.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) continues to have a profound impact on infant health care and health outcomes. In this study, we aimed to characterize the social impact of the first COVID-19 lockdown on families in a neonatal follow-up program (NFP). Given the ongoing increased use of telehealth across the medicine, we also evaluated for patient-level differences in virtual visit rates to identify patients at risk of follow-up challenges. STUDY DESIGN: To assess the impact of virtual health care utilization, we conducted a retrospective cohort study to describe challenges associated with telemedicine use in this vulnerable patient population during our telemedicine epoch (March 13, 2020-July 31, 2020). We also looked for patient-level factors associated with attending NFP visits as scheduled. Finally, we summarized caregiver responses to a COVID-19 Obstacles Assessment Survey and assessed for racial disparities in these responses. RESULTS: When comparing patients who completed their virtual visit to those who did not, we found no differences by infants' sex, birthweight, gestational age at birth, or caregiver self-reported race and ethnicity. However, infants whose visits did not occur were more often discharged with equipment or covered by public insurance. Nine percent of families reported food insecurity. CONCLUSION: During the initial COVID-19 lockdown, families with infants discharged from a neonatal intensive care unit (NICU) faced significant obstacles caring for their infants and attending scheduled follow-up visits. Infants in families with lower socioeconomic status or with increased medical complexity faced increased challenges in attending virtual follow-up visits during this epoch. Given the ongoing reliance on telemedicine in health care and the need to better prepare for future epidemics/pandemics, this study offers critical information that can assist neonatal teams in bolstering transitions to home and creating stronger safety nets for their patients after discharge. KEY POINTS: · Telemedicine works well for high-risk neonatal populations.. · Infant medical complexity may be a risk factor for challenges attending neonatal follow-up visits.. · NICUs should work to prevent food insecurity postdischarge..

Urinary liver-type fatty acid-binding protein is independently associated with graft failure in outpatient kidney transplant recipients.

Urinary liver-type fatty acid-binding protein (uL-FABP) is a biomarker of kidney hypoxia and ischemia, and thus offers a novel approach to identify early kidney insults associated with increased risk of graft failure in outpatient kidney transplant recipients (KTR). We investigated whether uL-FABP is associated with graft failure and whether it improves risk prediction. We studied a cohort of 638 outpatient KTR with a functional graft ≥1-year. During a median follow-up of 5.3 years, 80 KTR developed graft failure. uL-FABP (median 2.11, interquartile range 0.93-7.37 µg/24"/>h) was prospectively associated with the risk of graft failure (hazard ratio 1.75; 95% confidence interval 1.27-2.41 per 1-SD increment; P = .001), independent of potential confounders including estimated glomerular filtration rate and proteinuria. uL-FABP showed excellent discrimination ability for graft failure (c-statistic of 0.83) and its addition to a prediction model composed by established clinical predictors of graft failure significantly improved the c-statistic to 0.89 (P for F-test <.001). These results were robust to several sensitivity analyses. Further validation studies are warranted to evaluate the potential use of a risk-prediction model including uL-FABP to improve identification of outpatient KTR at high risk of graft failure in clinical care.

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin-angiotensin-aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. METHODS: We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. RESULTS: A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference -0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) -0.83 to -0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5-4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI -0.46 to -0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05-2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50-1.29), P = 0.4]. CONCLUSIONS: These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant Polycystic Liver and Kidney Disease.

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.

Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers.

BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints.

COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration.

BACKGROUND: Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. METHODS: We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. RESULTS: Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3-30.2%] in kidney transplant and 25.0% (95% CI 20.2-30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59-1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation <1 year before presentation (HR adjusted for sex, age and frailty 0.20, 95% CI 0.07-0.56, P < 0.01). CONCLUSIONS: The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Machine-learning-based early prediction of end-stage renal disease in patients with diabetic kidney disease using clinical trials data.

AIM: To predict end-stage renal disease (ESRD) in patients with type 2 diabetes by using machine-learning models with multiple baseline demographic and clinical characteristics. MATERIALS AND METHODS: In total, 11 789 patients with type 2 diabetes and nephropathy from three clinical trials, RENAAL (n = 1513), IDNT (n = 1715) and ALTITUDE (n = 8561), were used in this study. Eighteen baseline demographic and clinical characteristics were used as predictors to train machine-learning models to predict ESRD (doubling of serum creatinine and/or ESRD). We used the area under the receiver operator curve (AUC) to assess the prediction performance of models and compared this with traditional Cox proportional hazard regression and kidney failure risk equation models. RESULTS: The feed forward neural network model predicted ESRD with an AUC of 0.82 (0.76-0.87), 0.81 (0.75-0.86) and 0.84 (0.79-0.90) in the RENAAL, IDNT and ALTITUDE trials, respectively. The feed forward neural network model selected urinary albumin to creatinine ratio, serum albumin, uric acid and serum creatinine as important predictors and obtained a state-of-the-art performance for predicting long-term ESRD. CONCLUSIONS: Despite large inter-patient variability, non-linear machine-learning models can be used to predict long-term ESRD in patients with type 2 diabetes and nephropathy using baseline demographic and clinical characteristics. The proposed method has the potential to create accurate and multiple outcome prediction automated models to identify high-risk patients who could benefit from therapy in clinical practice.

Evaluating Glomerular Filtration Rate Slope as a Surrogate End Point for ESKD in Clinical Trials: An Individual Participant Meta-Analysis of Observational Data.

BACKGROUND: Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR. METHODS: To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m2 and 122,664 participants with eGFR<60 ml/min per 1.73 m2 from 14 cohorts followed for an average of 4.2 years. RESULTS: Slower eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m2 (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m2 (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%. CONCLUSIONS: Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m2, but those with the highest risk would be expected to benefit the most.

The role of the innate immune system on pulmonary infections.

Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.

Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

BACKGROUND: Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline. METHODS: The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up. RESULTS: UPCR and TC response varied between individuals: mean UPCR response was -1.3% (5th-95th percentile -59.9 to 141.8) and mean TC response was -93.9 mg/dL (-169.1 to -26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) -1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI -1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6-3.0; P = 0.004 and 1.7; 95% CI 0.5-2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5-3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin. CONCLUSIONS: Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.

Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes.

AIM: To assess the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin on a pre-specified panel of 13 urinary metabolites linked to mitochondrial metabolism in people with type 2 diabetes and elevated urine albumin levels. MATERIALS AND METHODS: Urine and plasma samples were used from a double-blind, randomized, placebo-controlled crossover trial in 31 people with type 2 diabetes, with an albumin:creatinine ratio >100 mg/g, and who were on a stable dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Dapagliflozin or placebo treatment periods each lasted 6 weeks, with a 6-week washout period in between. Urinary and plasma metabolites were quantified by gas-chromatography mass spectrometry, corrected for creatinine level, and then combined into a single-valued urinary metabolite index. Fractional excretion of the metabolites was calculated. RESULTS: All 13 urinary metabolites were detectable. After 6 weeks of dapagliflozin therapy, nine of the 13 metabolites were significantly increased from baseline. The urinary metabolite index increased by 42% (95% confidence interval [CI] 8.5 to 85.6; P = .01) with placebo versus 121% (95% CI 69 to 189; P < .001) with dapaglifozin. The placebo-adjusted effect was 56% (95% CI 11 to 118; P = .012). In plasma, seven of the 13 metabolites were detectable, and none was modified by dapagliflozin. CONCLUSIONS: Dapagliflozin significantly increased a panel of urinary metabolites previously linked to mitochondrial metabolism. These data support the hypothesis that SGLT2 inhibitors improve mitochondrial function, and improvements in mitochondrial function could be a mechanism for kidney protection. Future studies with longer treatment duration and clinical outcomes are needed to confirm the clinical impact of these findings.

Diabetes mellitus comorbidity in patients enrolled in tuberculosis drug efficacy trials around the world: A systematic review.

AIMS: With a prevalence of 16%, diabetes mellitus (DM) is one of the most frequent non-communicable comorbidities of tuberculosis (TB). DM is a major risk factor for adverse TB outcomes and may require personalized TB drug dosing regimens. However, information on the inclusion of DM in TB drug trials is lacking. We aimed to assess the percentage of recent TB drug efficacy trials that included DM patients. METHODS: A systematic review was performed and reported according to PRISMA guidelines. PubMed, Science Direct, and ClinicalTrials.gov databases were systematically searched for TB drug trials published between 1 January 2012 and 12 September 2017. Primary outcome was the percentage of TB drug trials performed around the world that included DM patients. RESULTS: Out of the included 41 TB drug trials, 12 (29.3%) reported DM comorbidity among the study participants. Nine trials (21.9%) excluded all patients with DM comorbidity, ten (24.4%) excluded only insulin-dependent or uncontrolled DM, and 10 (24.4%) did not mention whether DM was included or excluded. Of the 12 trials that included DM comorbidity, the majority did not report the diagnostic criteria for DM and none reported outcomes in the DM subpopulation. Inclusion of DM was higher in drug-resistant-TB trials (67%, P = .003, vs drug-susceptible) and trials performed in Asia (60%, P = .006, vs Africa). CONCLUSIONS: Fewer than 1/3 recent TB drug trials reported the inclusion of DM. To better reflect real-world DM prevalence and differential TB drug effectiveness, inclusion of DM patients requires increased attention for future TB drug trials.

Personalized medicine in diabetic kidney disease: a novel approach to improve trial design and patient outcomes.

PURPOSE OF REVIEW: In the last decade many attempts have been made to reduce the high residual risk of end-stage kidney disease and cardiovascular disease in patients with diabetic kidney disease by targeting a variety of risk markers. Subsequent analyses revealed that the variation in individual drug response to the tested interventions partly explains why these trials did not result in additional kidney or cardiovascular protection. This review summarizes recent insights regarding individual variation in drug response. Additionally, we explore novel approaches to incorporate this drug response variability in the design of new clinical trials. RECENT FINDINGS: Recent studies suggest that a plausible explanation for individual therapy resistance emanates from intrinsic individual characteristics such as genetic make-up or volume status and is likely only partially explained by drug characteristics such as the dose or type of intervention. Biomarker-based enrichment strategies to identify high-risk individuals and/or those who are more likely to respond to interventions offer opportunities to tailor therapies to individual patients. SUMMARY: Individual drug response variability is a recognized phenomenon in clinical practice. It is time to implement novel approaches that take into account this response variability in the design of new trials in diabetic kidney disease in order to define optimal therapies for individual patients.

Implementing personalized medicine in diabetic kidney disease: Stakeholders' perspectives.

The promise of personalized medicine to deliver "the right treatments at the right time to the right person" is the next frontier in healthcare. However, to implement personalized medicine in chronic diseases such as diabetes mellitus and diabetic kidney disease (DKD), a number of different aspects need to be taken into account. Better risk stratification and more precise options for treatment need to be developed and included in clinical practice guidelines. A patient's unique psychological, social and environmental situation also drive disease progression and outcomes. Appraising the cost effectiveness of precision medicines is necessary, not just as the cost of new therapies, but also the cost of diagnosis with novel methodologies and averted complications. As the prevalence of DKD grows worldwide to epidemic proportions, challenges such as global disparities in resources, access to healthcare and prevalence need to be addressed. This review considers these issues to achieve the short and longer-term goals of implementing personalized medicine in clinical practice.

Individual variability in response to renin angiotensin aldosterone system inhibition predicts cardiovascular outcome in patients with type 2 diabetes: A primary care cohort study.

AIMS: To assess variability in systolic blood pressure (SBP) and albuminuria (urinary albumin creatinine ratio [UACR]) responses in patients with type 2 diabetes mellitus initiating renin angiotensin aldosterone system (RAAS) inhibition, and to assess the association of response variability with cardiovascular outcomes. MATERIAL AND METHODS: We performed an observational cohort study in patients with type 2 diabetes who started RAAS inhibition between 2007 and 2013 (n = 1600). Patients were identified from general practices in the Netherlands. Individual response in SBP and UACR was assessed during 15 months' follow-up. Patients were categorized as: good responders (∆SBP <0 mm Hg and ∆UACR <0%); intermediate responders (∆SBP <0 mm Hg and ∆UACR >0% or ∆SBP >0 mm Hg and ∆UACR <0%); or poor responders (∆SBP >0 mm Hg and ∆UACR >0%). Multivariable Cox regression was performed to test the association between initial RAAS inhibition response and subsequent cardiovascular outcomes. RESULTS: After starting RAAS inhibition, the mean SBP change was -13.2 mm Hg and the median UACR was -36.6%, with large between-individual variability, both in SBP [5th to 95th percentile: 48.5-20] and UACR [5th to 95th percentile: -87.6 to 171.4]. In all, 812 patients (51%) were good responders, 353 (22%) had a good SBP but poor UACR response, 268 (17%) had a good UACR but poor SBP response, and 167 patients (10%) were poor responders. Good responders had a lower risk of cardiovascular events than poor responders (hazard ratio 0.51, 95% confidence interval 0.30-0.86; P = .012). CONCLUSIONS: SBP and UACR response after RAAS inhibition initiation varied between and within individual patients with type 2 diabetes treated in primary care. Poor responders had the highest risk of cardiovascular events, therefore, more efforts are needed to develop personalized treatment plans for these patients.