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OBJECTIVE: Diabetic kidney disease favors diabetic foot ulcers, however we do not know whether the reverse relation exists. We investigated whether diabetic foot disease (DFD) related to an increased risk of developing renal events. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of a cohort of patients hospitalized for type 2 diabetes mellitus (T2DM) between 2009 and 2017, stratified for the risk of diabetic foot ulcer grades 0 (no risk), 1 and 2 (at risk), and 3 (DFD) according to the International Work Group on Diabetic Foot (IWGDF) classification. We highlighted new renal events (end-stage renal disease or a doubling of serum creatinine) in their medical records until December 2020. The relationship between DFD and later renal events was analyzed by multivariable Cox regression model. RESULTS: Among 519 patients, 142 (27 %) had a DFD at baseline, and 159 (30 %) were classified as Grades 1 or 2. Thirty-six renal events occurred during the 54 ± 27 months of follow-up: 19 subjects started dialysis, 1 had a renal transplantation, and 16 had a doubling of serum creatinine: 15 each in subjects with DFD and subjects at risk, versus 6 in subjects with Grade 0 DFD (logrank: P = 0.001). Adjusted for i) age and sex; ii) hyperglycemic exposure; iii) conventional cardiovascular risk factors; iv) renal parameters: and v) new diabetic foot ulcers during follow-up, DFD (HR 2.7 to 5.9) and being at risk of DFD Grades 1-2 (HR 2.8 to 5.1) were significantly related to new renal events. CONCLUSION: The risk of renal events was increased in people with T2DM and DFD.

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Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.

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Since it is widely accepted that there is a positive correlation between the salt intake and hypertension or cerebro-cardiovascular-renal events, salt intake restriction is currently widely recommended, especially in patients with hypertension. However, salt intake restriction does not always have beneficial effects. Indeed, an excessively low salt intake has been reported to be harmful to health. While a reasonable vegetable and fruit intake reportedly decreases blood pressure, whether or not vegetable and fruit intake truly leads to reductions in cerebro-cardiovascular-renal events or all-cause mortality remains unclear. We reviewed the importance of vegetable and fruit intake for health, focusing on the relationship between urinary potassium excretion, a marker of vegetable and fruit intake, and cerebro-cardiovascular-renal events or all-cause mortality. In conclusion, vegetable and fruit intake may be essential for reducing cerebro-cardiovascular-renal events and all-cause mortality.

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Aim: The incidence of cardiovascular and renal events was investigated in patients with type 2 diabetes who were classified according to anemia and the components of dialysis-independent chronic kidney disease (CKD) in a prospective observational study. Methods: A population of 778 Japanese patients with type 2 diabetes was prospectively analyzed for 4 years. The outcomes were the incidence of cardiovascular events and renal events. Results: In all subjects, the incidence of cardiovascular and renal events was found to be 5% and 11%, respectively. Even after adjusting for a reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), the incidence of cardiovascular events was significantly higher (hazard ratio [HR]: 5.73) in patients with anemia and albuminuria than in those without anemia and albuminuria. The incidence of renal events was significantly higher in patients with no anemia and albuminuria (HR: 2.93) and further in those with anemia and albuminuria (HR: 7.56) than in those without anemia and albuminuria even after adjusting for a reduced eGFR. Conclusion: Anemia combined with albuminuria is a risk factor for vascular events in patients with type 2 diabetes, regardless of the eGFR. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00637-x.

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Objectives: Cardiovascular and renal diseases are closely related. Brain natriuretic peptide (BNP) and urinary albumin are established predictors for cardiac and renal morbidities, respectively. To date, no reports have investigated the combined predictive value of BNP and urinary albumin for long-term cardiovascular-renal events in patients with chronic kidney disease (CKD). The aim of this study was to investigate this theme. Methods: Four hundred eighty-three patients with CKD were enrolled into this study and followed-up for 10 years. The endpoint was cardiovascular-renal events. Results: During the median follow-up period of 109 months, 221 patients developed cardiovascular-renal events. Log-transformed BNP and urinary albumin were identified as independent predictors for cardiovascular-renal events, with a hazard ratio of 2.59 (95% confidence interval [CI], 1.81-3.72) and 2.27 (95% CI, 1.82-2.84) for BNP and urinary albumin, respectively. For the combined variables, the group with high BNP and urinary albumin had a markedly higher risk (12.41-times; 95% CI 5.23-29.42) of cardiovascular-renal events compared with that of the group with low BNP and urinary albumin. Adding both variables to a predictive model with basic risk factors improved the C-index (0.767, 0.728 to 0.814, p=0.009), net reclassification improvement (0.497, p<0.0001), and integrated discrimination improvement (0.071, p<0.0001) more than each of them alone. Conclusions: This is the first report to demonstrate that the combination of BNP and urinary albumin can stratify and improve the predictability of long-term cardiovascular-renal events in CKD patients.

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BACKGROUND: The aim of this study was to evaluate the prognostic value of automated office blood pressure (AOBP) measurement in patients with hypertension and chronic kidney disease (CKD) stage 3-5 not on dialysis. METHODS: At baseline, 140 patients were recruited, and blood pressure (BP) measurements with 3 different methods, namely, office blood pressure (OBP), AOBP, and ambulatory blood pressure measurement (ABPM), were recorded. All patients were prospectively followed for a median period of 3.4 years. The primary outcome of this study was a composite outcome of cardiovascular (CV) events (both fatal and nonfatal) or a doubling of serum creatine or progression to end-stage kidney disease (ESKD), whichever occurred first. RESULTS: At baseline, the median age of patients was 65.2 years; 36.4% had diabetes; 21.4% had a history of CV disease; the mean of estimated glomerular filtration rate (eGFR) was 33 mL/min/1.73 m2; and the means of OBP, AOBP, and daytime ABPM were 151/84 mm Hg, 134/77 mm Hg, and 132/77 mm Hg, respectively. During the follow-up, 18 patients had a CV event, and 37 patients had a renal event. In the univariate cox regression analysis, systolic AOBP was found to be predictive of the primary outcome (HR per 1 mm Hg increase in BP, 1.019, 95% CI 1.003-1.035), and after adjustment for eGFR, smoking status, diabetes, and a history of CV disease and systolic and diastolic AOBP were also found to be predictive of the primary outcome (HR per 1 mm Hg increase in BP, 1.017, 95% CI 1.002-1.032 and 1.033, 95% CI 1.009-1.058, respectively). CONCLUSIONS: In patients with CKD, AOBP appears to be prognostic of CV risk or risk for kidney disease progression and could, therefore, be considered a reliable means for recording BP in the office setting.

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To conduct a systematic review and meta-analysis of specific chronic kidney disease (CKD) trials focusing on the composite of cardiorenal outcome, and assess indirectly the clinical outcome of treatments with three inhibitors of sodium-glucose cotransporter-2 (SGLT2) by Bayesian network meta-analysis, we used PubMed and Embase for randomized controlled trials comparing the efficacy of SGLT2 inhibitors in patients with established CKD. We estimated the composite of cardiorenal outcome of SGLT2 inhibitors versus control by pairwise meta-analysis. We included three trials including four treatment strategies (canagliflozin, dapagliflozin, sotagliflozin, and placebo) that met our inclusion criteria. SGLT2 inhibitors reduced the composite of cardiorenal outcome by 27.5% (OR 0.70, 95% CI 0.57-0.86, I2 = 72%). Results were corroborated in subgroup analysis. SGLT2 inhibitors reduced the composite of cardiorenal outcome in patients with and without diabetes (OR 0.72, 95% CI 0.60-0.86, and OR 0.51, 95% CI 0.35-0.75, respectively). The composite of cardiorenal outcome showed no significant difference in the comparison among three drugs: canagliflozin and dapagliflozin (OR 1.14, 95% CI 0.46-3.16), canagliflozin and sotagliflozin (OR 0.79, 95% CI 0.30-2.06), dapagliflozin and sotagliflozin (OR 0.69, 95% CI 0.26-1.73). Dapagliflozin was identified as having the lowest risk of the composite of cardiorenal outcome. In conclusion, SGLT2 inhibitors have robust benefits on the composite of cardiorenal outcome in patients with CKD. There was no significant difference in the composite of cardiorenal outcome among treatments with three SGLT2 inhibitors; however, dapagliflozin may be associated with the lowest risk of the composite of cardiorenal outcome.

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BACKGROUND: Hypertension is one of the risk factors for cerebro-cardiovascular and renal (CCR) diseases. High blood pressure is affected by the amount of salt (NaCl) and potassium (K) intake. There are many studies reporting the relationship between urinary sodium or potassium excretion and CCR events or all-cause mortality in general populations. Thus, it is necessary to investigate the relationship between urinary NaCl or K excretion and CCR events or all-cause mortality in hypertensive patients under control with anti-hypertensive drugs. METHODS: A prospective, multi-center cohort study was performed in 3210 hypertensives under treatment with anti-hypertensive drugs for 5 years. The primary outcome was the CCR events, and the secondary outcome was all-cause mortality. A time-dependent Cox proportional hazards regression analysis was performed to assess the association between outcomes and urinary NaCl and K excretion, blood pressure, or heart rate. RESULTS: During the follow-up period, 61 CCR events and 110 all-cause deaths occurred. There was no association between urinary NaCl excretion and CCR events or all-cause mortality. Lower urinary K excretion and higher Na/K ratio were associated with higher risk of CCR events or all-cause mortality. The CCR events were not associated with systolic, diastolic blood pressure, or heart rate. CONCLUSION: Lower urinary K excretion was associated with higher risk of CCR events or all-cause mortality in hypertensive patients under treatment with anti-hypertensive drugs.

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OBJECTIVES: To describe and compare baseline characteristics, healthcare and drug utilization, and negative clinical outcomes of commercially-insured patients diagnosed with OA of the hip and/or knee who initiated treatment on traditional oral NSAIDs (tNSAIDs), topical NSAIDs, or cyclooxygenase-2 inhibitors (COX-2s). METHODS: A commercial claims database (1/2012-3/2017) was used to identify patients ≥18 years old, with ≥2 diagnoses of hip and/or knee OA, and ≥90 days supply of NSAIDs. Patients were assigned to cohorts based on the type of NSAID initially prescribed and observed in the 6 months before (baseline) and 36 months after (follow-up) the date of their first NSAID prescription after the first OA diagnosis. Analyses estimated baseline demographic and clinical characteristics and follow-up period drug utilization. Logistic regressions assessed the risk of gastrointestinal (GI) and acute renal failure (ARF) events. RESULTS: tNSAIDs were the most frequently prescribed treatment. During the follow-up period, less than 15% of patients prescribed tNSAIDs switched to either COX-2s or topical NSAIDs and 37% of patients prescribed a COX-2 and 56% of patients prescribed a topical NSAID switched to tNSAIDs. GI and ARF events during the follow-up period ranged from 7.3-8.1% and 8.0-11.0%, respectively, across cohorts. The tNSAIDs and COX-2s cohorts had increased risk of both types of events relative to patients prescribed topical NSAIDs, controlling for other characteristics. CONCLUSIONS: Analyses characterize the long-term real-world utilization of NSAIDs and associated outcomes for patients with OA of the hip and/or knee. Study results highlight the likelihood of switching and the risk of negative clinical outcomes associated with long-term use.

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BACKGROUND: While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. METHODS: We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. RESULTS: Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)]. CONCLUSION: NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.

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PURPOSE: This study aimed to assess the safety risks associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) in elderly patients (≥65 years) compared with younger patients (<65 years) with osteoarthritis (OA) and/or chronic low back pain (CLBP). METHODS: A retrospective analysis was conducted on anonymized claims data of patients prescribed NSAIDs for OA and/or CLBP from 2009 to 2018 using hospital-based administrative database-Medical Data Vision (MDV). The key outcome was the incidence of developing gastrointestinal (GI), renal, and acute myocardial infarction (AMI) that are well-known events associated with NSAID use. RESULTS: Of 288,715 patients included, 23.7%, 60.5%, and 15.8% had OA, CLBP, or both, respectively. Elderly patients used non-oral NSAIDs more frequently than oral NSAIDs (57.8% and 38.7%, respectively), whereas younger patients showed comparable use (50.7% and 52.8%, respectively). The incidence of events per 10,000 person-years (95% CI) was higher in the elderly than in younger patients: GI, 29.68(27.67-31.68) vs. 16.61(14.60-18.63); renal, 124.77(120.56-128.99) vs. 39.88(36.72-43.03); and AMI, 27.41(25.48-29.35) vs. 10.90(9.27-12.53), respectively. After adjusting for covariates, the increase in risk for these events was seen in patients >70 years compared with younger patients (18-30 years) and was remarkable in patients >80 years with 2-fold, 10-fold, and 7-fold higher risk for developing GI, renal, and AMI events, respectively. CONCLUSION: Risk for developing NSAID-associated events was higher in the elderly; particularly, renal and AMI events that remarkably increased in patients >80 years. To reduce them, NSAIDs should be prescribed at the lowest effective dose for the shortest duration possible.

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Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. Study design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24–120). Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242–128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. (AU)

El objetivo de este estudio es realizar un mapa del tratamiento actual de la enfermedad de Fabry en España, analizando el efecto de diferentes factores en el desarrollo de eventos clínicos a largo plazo. Diseño del estudio: Análisis observacional retrospectivo multicéntrico. Criterios de inclusión: pacientes diagnosticados y tratados de enfermedad de Fabry. Se recogieron datos generales en relación con el diagnóstico, síntomas y tipo mutación, tipo de tratamiento recibido, evolución renal y cardiológica. Durante un tiempo de seguimiento de 60 meses (24-120), se recogió el primer evento clínico tras el inicio de tratamiento sustitutivo enzimático definido como mortalidad, evento renal, cardiológico o neurológico. Resultados: Se incluyeron 69 pacientes (42 H, 27 M) con una edad media de 44,6±13,7 años. A los cinco años de tratamiento, el FGe y la hipertrofia ventricular izquierda se mantuvieron estables, y la albuminuria tiende a disminuir, siendo este descenso más significativo en el grupo de pacientes tratados con beta-galactosidasa (de 242 a 128mg/g (p=0,05). Veintiún pacientes sufrieron un evento clínico (30%): seis renales, dos neurológicos y 13 cardiológicos (incluidas tres muertes). Los pacientes con ERC (FGe<60) antes del inicio de tratamiento tuvieron más eventos (log-rank 12.423, p=0,001), manteniéndose la predicción si excluíamos los eventos renales (log-rank 4.086 (p=0,043) en hombres y mujeres. La peor función renal al inicio del tratamiento aumentó entre tres y siete veces el riesgo de eventos clínicos en diferentes modelos de Cox ajustados. Conclusiones: La función renal al inicio de tratamiento sustitutivo enzimático es la principal predictora de desarrollo de eventos clínicos a largo plazo, tanto en hombres como mujeres. El inicio de tratamiento sustitutivo enzimático precoz antes del desarrollo de ERC mejoraría el pronóstico. (AU)

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BACKGROUND: Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. METHODS: A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. RESULTS: At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. CONCLUSIONS: Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

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INTRODUCTION: Several clinical studies and meta-analyses have demonstrated lower incidence of adverse renal and cardiovascular outcomes associated with the use of iso-osmolar contrast media (IOCM) than low-osmolar contrast media (LOCM) in patients with variable risk profiles undergoing intra-arterial interventional procedures. However, the association of contrast-type and major adverse renal and cardiovascular events (MARCE) has not been studied via comprehensive and robust real-world data analyses in patients with comorbid conditions considered at risk for post-procedural acute kidney injury (AKI). The objective of this study was therefore to retrospectively assess the MARCE rates comparing IOCM with LOCM in at-risk patients receiving iodinated intra-arterial contrast media using a real-world inpatient data source. METHODS: Patients who underwent a diagnostic or treatment procedure with intra-arterial IOCM or LOCM administration were identified using the Premier Healthcare Database. Patient subgroups including those with diabetes, heart failure, chronic kidney disease (CKD) stages 1-4, CKD 3-4, or diagnosis of chronic total occlusion (CTO) were formed. Subgroups with combinations of diabetes and CKD 3-4 with and without CTO were also investigated. We compared the primary endpoint of MARCE (composite of AKI, AKI requiring dialysis, acute myocardial infarction, stroke/transient ischemic attack, stent occlusion/thrombosis, or death) after IOCM versus LOCM administration via adjusted multivariable regression analyses. RESULTS: A total of 536,013 inpatient visits met the primary inclusion and exclusion criteria (IOCM = 133,192; LOCM = 402,821). After multivariable modeling, the use of IOCM was associated with a significantly lower incidence of MARCE than LOCM in patients with CKD 1-4, CKD 3-4, diabetes, or heart failure, with greatest absolute risk reduction (ARR) of 2.4% (p < 0.0001) in CKD 3-4 patients (relative risk reduction [RRR] = 13.8%, number needed to treat [NNT] = 43). Additionally, ARR associated with IOCM increased to 3.5% (p < 0.0001) in patients with combined comorbidities of diabetes and CKD 3-4 (RRR = 19.1%, NNT = 29). Statistically significant risk reduction was also found for the use of IOCM among patients who underwent revascularization for CTO (ARR = 1.6% [p < 0.0001], RRR = 22.3%, NNT = 62). CONCLUSION: Intra-arterial administration using IOCM in at-risk patients is associated with lower rates of MARCE than the use of LOCM. This difference is especially apparent in patients with a combination of CKD 3-4 and diabetes and in patients with CTO, providing real-world data validation with meaningful NNT in favor of IOCM.

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Objective: We aimed to evaluate the efficacy of canagliflozin for the treatment of specific cardiovascular and renal outcomes in Type 2 diabetes mellitus (T2DM) patients by means of a systematic review and meta-analysis. Methods: We performed comprehensive searches of PubMed, the Cochrane Library, and Embase for randomized, placebo-controlled trials of the treatment of T2DM with canagliflozin that were published to 28 September 2020. The cardiovascular outcomes recorded were cardiovascular mortality, heart failure, myocardial infarction, and stroke. The renal composite outcomes recorded were end-stage renal disease (ESRD), renal death. The data for the principal cardiovascular outcomes, ESRD, and renal death were pooled and expressed as Hazard ratios (HRs) with 95% confidence intervals (CIs). Two reviewers independently selected the trials and extracted the data. Results: We identified a total of 1,741 publications, leaving 96 for their titles, abstracts and full-text review. Of these, 10 trials met the inclusion criteria and were finally included in our meta-analysis. The meta-analysis showed that canagliflozin significantly reduced the risk of heart failure in T2DM by 36% (HR 0.64, 95% CI 0.53 to 0.77, p = 0.000). The effects of canagliflozin on non-fatal myocardial infarction or non-fatal stroke (HR 0.84, 95% CI: 0.76 to 0.93, p = 0.001), cardiovascular mortality (HR 0.84, 95% CI 0.72 to 0.97, p = 0.021), and myocardial infarction (HR 0.84, 95% CI 0.70 to 1.00, p = 0.045) in patients with T2DM were relatively small, reducing the risks by 16%. In addition, canagliflozin reduced the risk of stroke in T2DM patients by 13% (HR 0.87, 95% CI 0.71 to 1.06, p = 0.166). Moreover, canagliflozin significantly reduced the risk of the composite renal event of ESRD or renal death by 36% (HR 0.64, 95% CI 0.54 to 0.75, p = 0.000). Conclusion: This meta-analysis suggests that canagliflozin protects against cardiovascular and renal outcomes in patients with T2DM. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], identifier [CRD42020210315].

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BACKGROUND: Hypothyroidism and low free triiodothyronine (FT3) syndrome [low FT3 levels with normal thyroid-stimulating hormone (TSH)] have been associated with reduced kidney function cross-sectionally in chronic kidney disease (CKD) patients with severely reduced estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Results on the prospective effects of impaired thyroid function on renal events and mortality for patients with severely reduced eGFR or from population-based cohorts are conflicting. Here we evaluated the association between thyroid and kidney function with eGFR (cross-sectionally) as well as renal events and mortality (prospectively) in a large, prospective cohort of CKD patients with mild to moderately reduced kidney function. METHODS: Thyroid markers were measured among CKD patients from the German Chronic Kidney Disease study. Incident renal endpoints (combined ESKD, acute kidney injury and renal death) and all-cause mortality were abstracted from hospital records and death certificates. Time to first event analysis of complete data from baseline to the 4-year follow-up (median follow-up time 4.04 years) of 4600 patients was conducted. Multivariable linear regression and Cox proportional hazards models were fitted for single and combined continuous thyroid markers [TSH, free thyroxine (FT4), FT3] and thyroid status. RESULTS: Cross-sectionally, the presence of low-FT3 syndrome showed a significant inverse association with eGFR and continuous FT3 levels alone showed a significant positive association with eGFR; in combination with FT4 and TSH, FT3 levels also showed a positive association and FT4 levels showed a negative association with eGFR. Prospectively, higher FT4 and lower FT3 levels were significantly associated with a higher risk of all-cause mortality (N events = 297). Per picomole per litre higher FT3 levels the risk of reaching the composite renal endpoint was 0.73-fold lower (95% confidence interval 0.65-0.82; N events = 615). Compared with euthyroid patients, patients with low-FT3 syndrome had a 2.2-fold higher risk and patients with hypothyroidism had a 1.6-fold higher risk of experiencing the composite renal endpoint. CONCLUSIONS: Patients with mild to moderate CKD suffering from thyroid function abnormalities are at an increased risk of adverse renal events and all-cause mortality over time.

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Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

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BACKGROUND/OBJECTIVES: Acute Kidney Injury (AKI), induced by Checkpoint Inhibitors therapies (CPI-induced AKI), is an uncommon but severe Immune-Related Adverse Event (IRAE). The aim was to describe the epidemiology, risks factors, clinical, and laboratory characteristics of these renal adverse events (AEs) in a real-life cohort treatment. DESIGN/PARTICIPANTS: Consecutive patients undergoing a checkpoint inhibitor (CPI) therapy at the Hôpital Lyon Sud from January 2015 to July 2017 were included. A systematic retrospective analysis of medical files was performed, monthly serum creatinine levels, associated treatments, and occurrence of other IRAEs data were collected. AKI episodes explained by classic AKI aetiologies (prerenal, obstructive, septic) were excluded from the analysis. RESULTS: CPI-induced AKI incidence was 3.7% (13/352) and appeared to be time-dependent (7.7% (11/143) for patients with >3 months of CPI exposure), ranging from 1 to 16 months. All cases with available histology were acute tubulointerstitial nephritis (ATIN), with poor urinary sediment. The severity of AKI was mild (stage 1 in 50% of cases), with no need for renal-replacement therapy. Although CPI-induced AKI patients had more frequently other IRAEs (77% versus 39%), this was not associated with a greater risk of AKI. Pre-existing chronic kidney disease (defined as an estimated glomerular filtration rate (eGFR) <60 ml/min) was not associated with a greater risk of CPI-induced AKI. Treatments of CPI-induced AKI were heterogeneous, with discontinuation of CPIs, and inconstant systemic corticosteroid therapy. CONCLUSION: The monitoring of renal function and early identification of AKI during CPIs treatment is essential. The optimal management of CPI-induced AKI remains unclear and requires a close collaboration between the oncology and nephrology departments. CLINICAL RELEVANCY STATEMENT: Immune checkpoint inhibitors (CPIs) have dramatically improved patient outcomes in different malignant contexts such as melanoma, non-small cell lung cancers (NSCLC) and urologic cancers. Usually well-tolerated, CPIs are however associated with immune-related adverse events (IRAEs). Among them, acute kidney injury (AKI) is uncommon, and not well-described. Following the exponential increase in the prescription of CPIs, previously uncommon cases of IRAEs (such as AKI) have become common occurrence in referral centres. Data regarding the epidemiology, risk factors, or management of CPI-induced AKI are currently lacking or can be discordant. Data regarding CPI-induced AKI, in a large real-life cohort were reported herein.

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INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have long-term benefits but are limited by side effects. We assessed the health and economic burden of renal events associated with NSAID use in patients with osteoarthritis (OA) and/or chronic low back pain (CLBP). METHODS: This retrospective, large-scale, medical claims database study of Japanese patients receiving NSAIDs for OA and/or CLBP between 2009 and 2018 assessed the incidence of renal events and effect of treatment duration, mode of administration, and usage consistency of NSAIDs. RESULTS: Of 180,371 patients, NSAIDs were prescribed as first-line analgesics in 89.3%. Incidence per 10,000 person-years (95% confidence interval [CI]) for renal events was 23.46 (21.84-25.08) and for progression of chronic kidney disease (CKD) was 267.12 (189.93-344.32). Longer treatment duration (> 1 to ≤ 3 years, risk ratio [RR] 1.32, 95% CI 1.12-1.54; P = 0.0007; > 3 to ≤ 5 years, RR: 1.38, 95% CI 1.04-1.84; P = 0.0254 vs. < 1 year) and consistent use (RR: 1.24, 95% CI 0.99-1.55; P = 0.0595) increased the risk of renal events but the latter did not reach statistical significance. The risk was similar in patients using patch/oral NSAIDs and high in elderly patients and in those with diabetes, hypertension, and other cardiovascular disease. Following a renal event, median 1-year cost of drug treatment was $27.90; hospitalization, $1779.40; and dialysis, $33,018.40. CONCLUSIONS: Risk of renal events significantly increased with prolonged and consistent NSAID use (irrespective of mode of administration), with age, and in patients with certain comorbidities. Careful NSAID use is recommended in patients with CKD and those at high risk for CKD.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in patients with osteoarthritis (OA) and/or chronic low back pain (CLBP) for pain relief but their use is limited by side effects. These side effects may include abdominal, heart, and kidney problems. This article presents the results from a large claims database study in Japan that assessed the incidence of renal events and the associated healthcare cost. Impact of NSAIDs treatment duration, mode of administration, and usage consistency on the risk of developing renal events was evaluated. Results showed high incidence of renal events and progression of chronic kidney disease. Longer treatment duration and consistent use increased the risk of developing renal events. The risk was similar in patients using patch/oral NSAIDs and high in elderly patients and those with diabetes, hypertension, and other heart diseases. The estimated cost of drug treatment, hospitalization, and dialysis was also high. The author of the study would recommend NSAIDs to be used carefully in patients at risk for (or with) chronic kidney disease.

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Purpose/Method: No studies have reported on prognostic markers in patients with chronic kidney disease (CKD) according to the severity of the disease. Therefore, in this multicenter, prospective trial performed as part of the Gunma CKD SPECT Multicenter Study, we recruited 311 patients with CKD (eGFR < 60 min/mL/1.73 m2) including 50 patients on hemodialysis and followed them for 2 years. The study sample underwent stress 99mTc-tetrofosmin SPECT for suspected or possible ischemic heart disease. We evaluated the summed stress score (SSS), summed rest score (SRS), summed difference score (SDS) and cardiac function with electrocardiogram-gated SPECT. Then, we compared the differences in prognostic markers for major adverse cardiac, cerebrovascular, and renal events (MACCRE) between patients with mild CKD (30 min/mL/1.73 m2 ≤ eGFR <60 min/mL/1.73 m2; n=184) and those with severe CKD (eGFR <30 min/mL/1.73 m2; n=97). Results: Of 281 patients available for analysis, 91 experienced MACCRE. In a multivariate Cox proportional hazards analysis of factors related to MACCRE, in patients with mild CKD the significant prognostic markers were SDS (P=0.002) and end-systolic volume (ESV, P=0.034); and in the patients with severe CKD, they were eGFR (P=0.03) and diabetes-mellitus (DM, P=0.023). Conclusions: Our findings indicate that SDS and ESV are significant prognostic markers for MACCRE in patients with mild CKD and eGFR and DM are significant prognostic markers in patients with severe CKD.