UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE.

Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full "lay" summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.

Incidence of tuberculosis is high in chronic kidney disease patients in South East England and drug resistance common.

The risk of tuberculosis (TB) is significantly increased in chronic kidney disease (CKD). Data on TB in CKD in the UK are sparse; most information stems from countries with high background prevalence. The aim of this study was to estimate the incidence of TB in CKD patients in South East London and to describe the epidemiology, treatment, and outcome. CKD patients with TB between 1994 and 2010 were identified retrospectively. Data were collected on type of renal replacement therapy, the method of TB diagnosis, disease site, treatment regimens, and risk factors. Forty patients were identified of whom 67.5% had CKD stages IV-V. Sixty-five percent were from non-UK born ethnic minorities. Median time from diagnosis of CKD to TB development was 12 months (range 0-192 months). Cumulative incidence of TB was 1267/100,000 [95% confidence interval (CI): 630-1904; 85 × background UK rate] in hemodialysis patients; 398/100,000 (95% CI: 80-1160; 26 × background UK rate) in peritoneal dialysis; and 522/100,000 (CI: 137-909; 35 × background UK rate) in transplant recipients. Sixty-three percent of patients had pulmonary TB and 25% of patients with culture-positive TB had resistant isolates. Fifty percent of patients were immunosuppressed due to drugs, diabetes, and/or retroviral disease. Treatment regimens were according to recent national guidance in 73% of cases. Seventy-six percent of patients experienced side effects. Greater awareness of risk factors, drug resistance, treatment regimens, and potential side effects is needed.

Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension.

BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1ß, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-ß, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.

The accuracy of diagnostic coding for acute kidney injury in England - a single centre study.

BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England. METHODS: We studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions. RESULTS: Against a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p < 0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72-87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI. CONCLUSIONS: Patients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010.

Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials.

BACKGROUND: The net absolute effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors across different patient groups have not been quantified. METHODS: We performed a meta-analysis of published large (>500 participants/arm) placebo-controlled SGLT-2 inhibitor trials after systematically searching MEDLINE and Embase databases from inception to 28th August 2021 (PROSPERO 2021 CRD42021240468). FINDINGS: Four heart failure trials (n=15,684 participants), four trials in type 2 diabetes mellitus at high atherosclerotic cardiovascular risk (n=42,568), and three trials in chronic kidney disease (n=19,289) were included. Relative risks (RRs) for all cardiovascular, renal and safety outcomes were broadly similar across these three patient groups, and between people with or without diabetes. Overall, compared to placebo, allocation to SGLT-2 inhibition reduced risk of hospitalization for heart failure or cardiovascular death by 23% (RR=0.77, 95%CI 0.73-0.80; n=6658), cardiovascular death by 14% (0.86, 0.81-0.92; n=3962), major adverse cardiovascular events by 11% (0.89, 0.84-0.94; n=5703), kidney disease progression by 36% (0.64, 0.59-0.70; n=2275), acute kidney injury by 30% (0.70, 0.62-0.79; n=1013 events) and severe hypoglycaemia by 13% (0.87, 0.79-0.97; n=1484). There was no effect of SGLT-2 inhibition on risk of non-cardiovascular death (0.93, 0.86-1.01; n=2226), but a net 12% reduction in all-cause mortality remained evident (0.88, 0.84-0.93; n=6188). However, the risk of ketoacidosis was 2-times higher among those allocated SGLT-2 inhibitors compared to placebo (2.03, 1.41-2.93; n=159; absolute excess in people with diabetes ∼0.3/1000 patient years). A small increased risk of urinary tract infection was evident (1.07, 1.02-1.13; n=5384) alongside a known increased risk of mycotic genital infections. Overall, risk of lower limb amputations was increased by 16% (1.16, 1.02-1.31; n=1074), but this risk was largely driven by a single outlying trial (CANVAS). INTERPRETATIONS: The relative effects of SGLT-2 inhibition on key safety and efficacy outcomes are consistent across the different studied groups of patient. Consequently, absolute benefits and harms are determined by the absolute baseline risk of particular outcomes, with absolute benefits on mortality and on non-fatal serious cardiac/renal outcomes substantially exceeding the risks of amputation and ketoacidosis in the main patient groups studied to date. FUNDING: MRC-UK & KRUK.