The renal function trajectory in clinical trial design: challenges and opportunities.

The changes in renal function over time as surrogate endpoints for new drug trials are complicated by many factors, including the often-expected initial decrease in estimated glomerular filtration rate when a new drug is started. Two articles in the journal address this challenge, but multiple other challenges are explored in this commentary. To maximize the benefits of expensive new drugs that may slow decline in renal function, these drugs should be reserved for those patients who have a high probability of rapid loss of kidney function.

Impact of Dapagliflozin Adjunctive Therapy on the Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes and Chronic Kidney Disease Stages 2-5: A systematic review and meta-analysis.

This meta-analysis investigated efficacy of dapagliflozin as adjunctive therapy for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stages 2-5. A systematic search was conducted of selected databases for randomised controlled trials that reported the mean change in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) from baseline. Out of 1,682 identified studies, 9 trials comprising 13,057 patients were included. A pooled estimate of 5 studies indicated that dapagliflozin did not affect eGFR; however, in 2 studies, it significantly reduced chronic eGFR decline compared to placebo (mean difference [MD] ± 2.74; 95% confidence interval [CI]: 1.55, 3.92; P <0.00001). Additionally, a pooled estimate of 4 studies showed that dapagliflozin significantly reduced UACR (MD -23.99%; 95% CI: -34.82--13.15; P <0.0001; I2 = 0%). Therefore, long-term use of dapagliflozin significantly attenuates eGFR decline and reduces albuminuria in patients with T2DM and CKD.

Effectiveness and safety of finerenone in diabetic kidney disease patients: a real-world observational study from China.

AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.

Kidney Outcomes Following Angiotensin Receptor-Neprilysin Inhibitor vs Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy for Thrombotic Microangiopathy.

Importance: Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established. Objective: To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA. Design, Setting, and Participants: This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023. Exposures: Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge. Main Outcomes and Measures: The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes. Results: Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison. Conclusions and Relevance: In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Renoprotective Effects of Daprodustat in Patients with Chronic Kidney Disease and Renal Anemia.

Many large-scale studies revealed that exogenous erythropoietin, erythropoiesis-stimulating agents, have no renoprotective effects. We reported the renoprotective effects of endogenous erythropoietin production on renal function in ischemic reperfusion injury (IRI) of the kidney using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat. The purpose of this study was to investigate the effects of daprodustat on the progression of chronic renal failure. We retrospectively investigated the effects of daprodustat on the progression of chronic renal failure and renal anemia in patients with stages 3a-5 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 mL/min/1.73 m2). The results show that daprodustat largely slowed the reduction in eGFR. The recovery of renal function was observed in some patients. Daprodustat is useful not only for renal anemia but also for the preservation of renal function. The renoprotective effect of daprodustat was small in patients with serum creatinine larger than 3-4 mg/dL because of low residual renal function. The appearance of renal anemia would be a sign of the time to start using daprodustat.

Effects of 6-month administration of tofogliflozin on cardiac function in elderly patients with heart failure with preserved ejection fraction: A retrospective study of a patient cohort.

Patients with type 2 diabetes mellitus are frequently hospitalized for heart failure. The ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'), measured by echocardiography, is a simple and convenient indicator of diastolic dysfunction. Various large clinical trials have reported that sodium glucose transporter-2 inhibitor therapy reduced cardiovascular events and hospitalizations in heart failure patients. We examined the effect of tofogliflozin on various physiological and cardiac function. A retrospective analysis was performed on elderly patients aged 65 years or older with type 2 diabetes mellitus attending Himi Municipal Hospital who were taking oral tofogliflozin 20 mg/day. Measurement of physiological and hormonal variables, blood sampling, and echocardiographic evaluations at 0, 1, 3, and 6 months were performed on those with ejection fraction (EF) of 40% or greater at the time of treatment. Statistical analysis was performed using t-tests and mixed-effects models, with brain natriuretic peptide less than or not less than 100 pg/mL, estimated glomerular filtration rate (eGFR) less than or not less than 50 mL/min/1.73 m2, and diuretics administered or not. Hypoglycemic effects were observed at 0, 1, 3, and 6 months. At each time point, EF was retained and E/e' was significantly reduced. On the other hand, most physiological parameters and laboratory results showed no clinical abnormalities. Mixed-effects models showed time-dependent reduction of E/e' in high/low brain natriuretic peptide, high/low eGFR, with or without diuretics between baseline and at 6 months. The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects.

Uric acid mediates the relationship between mixed heavy metal exposure and renal function in older adult people.

Background: Population aging is a pivotal trend observed globally, and the exposure to heavy metals can exacerbate the aging process and lead to kidney damage. However, the impact of combined heavy metal exposure on renal function among older individuals remains elusive. Our study employs machine learning techniques to delve into the effects and underlying mechanisms of mixed exposure to heavy metals on the renal function of the aging population. Methods: This study extracted comprehensive data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2015 and 2020. A total of 3,175 participants aged 60 years and above, with complete information on six metals - lead, cadmium, manganese, cobalt, mercury, and selenium, along with relevant covariates, were included in the study. To assess the impact of single or mixed metal exposure on the renal function of older adult individuals, various statistical techniques were employed: multiple logistic regression, weighted quantitative sum (WQS) regression, Bayesian kernel machine regression (BKMR), and mediation effects analysis. Results: Multiple logistic regression revealed that selenium and manganese were protective factors for chronic kidney disease (CKD). Cobalt was a risk factor for CKD. High concentrations of lead, cadmium, and cobalt were risk factors for urinary albumin creatinine ratio (ACR). WQS analyses revealed that mixed metal exposure was positively correlated with estimated glomerular filtration rate (eGFR) but negatively correlated with CKD. Selenium and manganese can neutralize the effects of other metals on eGFR. Mixed metal exposure was positively correlated with ACR, with lead and cadmium having a substantial effect. Mediation analysis showed that uric acid (UA) had a mediating effect of 9.7% and -19.7% in the association between mixed metals exposure and proteinuria and CKD, respectively. Conclusion: The impact of heavy metals on renal function in the older adult differs from that of adolescents and adults. This study suggests that elevated levels of mixed metals exposure are linked to proteinuria and CKD, with UA serving as a mediating factor.

The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

Kidney and Cardiovascular Effectiveness of SGLT2 Inhibitors vs GLP-1 Receptor Agonists in Type 2 Diabetes.

BACKGROUND: Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed. OBJECTIVES: The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D. METHODS: Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes. RESULTS: The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status. CONCLUSIONS: SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317).

Effects of environmental phenols on eGFR: machine learning modeling methods applied to cross-sectional studies.

Purpose: Limited investigation is available on the correlation between environmental phenols' exposure and estimated glomerular filtration rate (eGFR). Our target is established a robust and explainable machine learning (ML) model that associates environmental phenols' exposure with eGFR. Methods: Our datasets for constructing the associations between environmental phenols' and eGFR were collected from the National Health and Nutrition Examination Survey (NHANES, 2013-2016). Five ML models were contained and fine-tuned to eGFR regression by phenols' exposure. Regression evaluation metrics were used to extract the limitation of the models. The most effective model was then utilized for regression, with interpretation of its features carried out using shapley additive explanations (SHAP) and the game theory python package to represent the model's regression capacity. Results: The study identified the top-performing random forest (RF) regressor with a mean absolute error of 0.621 and a coefficient of determination of 0.998 among 3,371 participants. Six environmental phenols with eGFR in linear regression models revealed that the concentrations of triclosan (TCS) and bisphenol S (BPS) in urine were positively correlated with eGFR, and the correlation coefficients were ß = 0.010 (p = 0.026) and ß = 0.007 (p = 0.004) respectively. SHAP values indicate that BPS (1.38), bisphenol F (BPF) (0.97), 2,5-dichlorophenol (0.87), TCS (0.78), BP3 (0.60), bisphenol A (BPA) (0.59) and 2,4-dichlorophenol (0.47) in urinary contributed to the model. Conclusion: The RF model was efficient in identifying a correlation between phenols' exposure and eGFR among United States NHANES 2013-2016 participants. The findings indicate that BPA, BPF, and BPS are inversely associated with eGFR.

[Comparison of efficacy and safety of immunosuppressive therapy and rituximab targeting therapy in idiopathic membranous nephropathy].

Objective To assess the efficacy and safety of three treatment modalities (rituximab targeted B-cell therapy, calcium-phosphate inhibitor in conjunction with low-dose corticosteroids, and full-dose corticosteroids combined with cyclophosphamide) for patients at intermediate or high risk of idiopathic membranous nephropathy (IMN) and to analyze the factors impacting the remission rates of IMN. Methods A retrospective cohort study was conducted to analyze patients diagnosed with IMN in our nephrology department via renal biopsy, identifying a total of 148 patients at intermediate or high risk. These patients were categorized into three treatment groups: a RTX group with 60 patients receiving rituximab, a CNI group with 42 patients receiving calcineurin inhibitors, and a CTX group with 46 patients received cyclophosphamide. Baseline measurements of 24-hour urine protein, serum albumin, blood creatinine, uric acid, estimated glomerular filtration rate (eGFR), and serum anti-phospholipase A2 receptor antibody levels were recorded at the onset of the follow-up. Subsequently, changes in 24-hour urine protein, eGFR, remission rates, and occurrence of adverse events among the three patient groups were compared at 6, 12, and 18 months post-treatment. Moreover, COX regression analysis was employed to ascertain factors influencing the remission rate of IMN. Results At the outset of the follow-up period, no significant difference existed in baseline characteristics such as gender, age, 24-hour urine protein quantification, serum albumin, serum creatinine, uric acid, eGFR, serum anti-PLA2R antibody levels, body mass index (BMI), and systolic blood pressure among the patients, indicating the comparability of three groups. After 6 months, there were no notable changes in 24-hour urine protein quantification and eGFR among the three groups; however, remission rates in the RTX and CTX groups were lower than those in the CNI group. By the 12-month mark, 24-hour urine protein quantification in the RTX group significantly decreased compared to the CTX group, with overall remission rates showing no significant differences among the three groups. By the 18-month milestone, 24-hour urine protein quantification in the RTX group remained notably lower than that in the CTX group, with significantly higher eGFR levels. Additionally, the CTX group exhibited lower 24-hour urine protein quantification compared to the CNI group, with both RTX and CTX groups displaying higher remission rates than the CNI group. Predominant adverse reactions in the RTX group included infusion reactions and infections, whereas the CNI group were associated with metabolic syndrome and elevated serum creatinine, and the CTX group primarily experienced hepatic dysfunction. Multifactorial COX regression analysis revealed an association between baseline anti-PLA2R antibodies and remission rates of IMN (HR=1.162, 95% CI 1.078-1.249). Conclusion RTX therapy for IMN exhibits a gradual onset of action, boasting a superior disease remission rate at 18 months in comparison to CNI. It demonstrates a similarity to CTX in this aspect and offers prolonged maintenance of remission. Conversely, CNI demonstrates a rapid onset of action but poses a risk of exacerbating renal impairment in patients. Notably, elevated levels of serum anti-PLA2R antibodies emerge as an independent risk factor influencing remission in IMN.

Peripheral dopamine suppression and elevated cystatin C in early diabetic nephropathy in spontaneously diabetic rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F2α, an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Deciphering the kidney hemodynamic effects of SGLT2 inhibition: translating insights from rats to humans in type 2 diabetes.

The attenuation of glomerular hyperfiltration is posited to be a principal mechanism underlying the kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in diabetic kidney disease. Notably, the impact of SGLT2 inhibitors on kidney hemodynamic function has been posited to vary between type 1 and type 2 diabetes. The study by Wada et al. documents that in an animal model of type 2 diabetes, SGLT2 inhibitors mitigate glomerular hyperfiltration predominantly through afferent arteriolar constriction, a process mediated by the adenosine/A1 receptor pathway. This observation is consistent with mechanisms identified in type 1 diabetes, arguing for similar methods in type 1 and 2 diabetes.

NSAIDs, analgesics, antiplatelet drugs, and decline in renal function: a retrospective case-control study with SIDIAP database.

INTRODUCTION: We aim to explore the association between NSAIDs consumption, Symptomatic Slow Action Drugs for Osteoarthritis (SYSADOA), analgesics, and antiplatelet drugs, and decline in renal function by estimated Glomerular Filtration Rate (eGFR). METHODS: We performed a case-control study using the SIDIAP database in Catalonia. We considered defined cases, patients with an eGFR value ≤ 45 ml/min/1.73 m2 in the period 2010-2015 with a previous eGFR value ≥ 60, and no eGFR ≥ 60 after this period. Controls had an eGFR ≥ 60 with no previous eGFR < 60. Five controls were selected for each case, matched by sex, age, index date, Diabetes Mellitus and Hypertension. We estimated Odds Ratios (OR, 95% Confidence Intervals) of decline in renal function for drugs group adjusting with logistic regression models, by consumption measured in DDD. There were n = 18,905 cases and n = 94,456 controls. The mean age was 77 years, 59% were women. The multivariate adjusted model showed a low risk for eGFR decline for NSAIDs (0.92;0.88-0.97), SYSADOA (0.87;0.83-0.91) and acetaminophen (0.84;0.79-0.89), and an high risk for metamizole (1.07;1.03-1.12), and antiplatelet drugs (1.07;1.03-1.11). The low risk in NSAIDs was limited to propionic acid derivatives (0.92;0.88-0.96), whereas an high risk was observed for high doses in both acetic acid derivatives (1.09;1.03-1.15) and Coxibs (1.19;1.08-1.30). Medium and high use of major opioids shows a high risk (1.15;1.03-1.29). Triflusal showed high risk at medium (1.23;1.02-1.48) and high use (1.68;1.40-2.01). CONCLUSION: We observed a decline in renal function associated with metamizole and antiplatelet agent, especially triflusal, and with high use of acetic acid derivates, Coxibs, and major opioids. Further studies are necessary to confirm these results.

Real-world impact of adding a glucagon-like peptide-1 receptor agonist compared with basal insulin on metabolic targets in adults living with type 2 diabetes and chronic kidney disease already treated with a sodium-glucose co-transporter-2 inhibitor: The Impact GLP-1 CKD study.

AIM: To compare the effectiveness of adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with adding basal insulin among adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) already treated with a sodium-glucose co-transporter-2 inhibitor (SGLT2i) and not reaching their glycaemic control targets. METHODS: A retrospective analysis of the Canadian LMC Diabetes Registry was conducted. Adults who initiated a GLP-1 RA were matched 1:1 to adults who initiated basal insulin in a T2D and CKD population. Changes in metabolic outcomes were evaluated at 26-52 weeks following the therapy start date. RESULTS: Propensity score matching was used to match participants who initiated a GLP-1 RA to participants who initiated basal insulin (n = 153/cohort). A significantly greater reduction in HbA1c at 26-52 weeks of follow-up was observed in the GLP-1 RA cohort compared with the basal insulin cohort (-1.3% ± 1.4% vs. -1.1% ± 1.4%, P = .03). Weight was significantly reduced (-3.4 ± 3.7 vs. 2.6 ± 4.5 kg, P < .001), and the estimated glomerular filtration rate decline slowed significantly (-0.3 ± 8.2 vs. -2.4 ± 10.4 mL/min/1.73m2, P = .02), but the change in albuminuria was not significantly different (-5.7 ± 38.1 vs. -0.5 ± 38.3 mg/mmol, P = .47) at follow-up in the GLP-1 RA group compared with the basal insulin group. No differences in self-reported hypoglycaemic events per week and therapy discontinuations were reported between the cohorts. CONCLUSIONS: The study shows the real-world effectiveness of GLP-1 RA therapy for T2D and CKD. GLP-1 RAs provided superior reductions in HbA1c and weight, and greater kidney protection, compared with basal insulin among adults with T2D and CKD already treated with an SGLT2i.

Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Decreased Kidney Function Explains Higher Vancomycin Exposure in Older Adults.

INTRODUCTION: Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics. METHODS: This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression). RESULTS: We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFRCKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09). CONCLUSIONS: The absence of age as a significant factor in the multivariable analysis suggests that eGFRCKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM.

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

BACKGROUND AND OBJECTIVES: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). METHODS: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. RESULTS: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. CONCLUSION: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.