eGFR Trajectories Research Articles

Risk Stratification for Chronic Kidney Disease After Liver Transplant for Metabolic Dysfunction-associated Steatohepatitis (MASH) Cirrhosis: Results From the NailMASH Consortium.

Chronic kidney disease (CKD) is a well-recognized complication in patients undergoing liver transplantation (LT), particularly those with metabolic dysfunction-associated steatohepatitis (MASH), a leading cause of cirrhosis in the modern era. This study sought to refine risk stratification for CKD events post-LT in cirrhosis patients with MASH by leveraging baseline renal function at transplant. A total of 717 MASH cirrhosis patients who had LT (1997-2017) at 7 US centers (NailMASH Consortium) were analyzed. Patients were categorized by estimated glomerular filtration rate (eGFR) at transplant: low (LGFR, eGFR ≤30 mL/min/1.73 m²), medium (MGFR, eGFR >30-≤60 mL/min/1.73 m²), and high (HGFR, eGFR >60 mL/min/1.73 m²). Time-related eGFR intercepts, slopes, and assessments of advanced-stage CKD (aCKD) events, defined as 2 eGFR levels <30 mL/min/1.73 m² separated by ≥90 d, were examined. Post-LT, LGFR group showed increased eGFR, whereas the HGFR group experienced a decline. The 3-mo mark was identified as a "reset point," signifying a new reference level, beyond which a different rate of decline was observed. After 3 mo, mean eGFRs of the LGFR group approached MGFRs, whereas the mean eGFR of the HGFR group continued to decrease but remained higher than other groups during a 60-mo follow-up. LGFR patients had significantly higher aCKD probability than MGFR and HGFR groups. Subanalysis at 3 mo post-LT revealed more aCKD events in the LGFR group compared with MGFR and HGFR groups (P < 0.0001). The study underscores renal impact of LT in MASH cirrhosis, indicating unique eGFR trajectories post-LT tied to baseline eGFR, with a reset point at 3 mo. Monitoring post-LT renal function, especially in those at aCKD risk, is crucial. Renal-sparing immunosuppression may help, regardless of baseline eGFR. Further studies are needed for interventions addressing renal dysfunction of patients with MASH post-LT.

Kidney growth progression patterns in autosomal dominant polycystic kidney disease

BackgroundPrognosis for autosomal dominant polycystic kidney disease (ADPKD), the main inherited cause of kidney failure, relies on estimating cystic growth using linear formulas derived from height-adjusted total kidney volume (Ht-TKV). However, nonlinear renal growth patterns may occur in typical ADPKD. AimsTo determine kidney outcomes of subjects diagnosed with typical ADPKD exhibiting nonlinear, and unpredictable cystic growth during follow-up. MethodsRetrospective cohort study. We categorized TKV changes in individuals with typical ADPKD according to observed kidney growth trajectories. Ht-TKV was calculated from consecutive CT or MRI using the ellipsoid method. We compared estimated glomerular filtration rate (eGFR) trajectories with linear mixed models. ResultsWe included 83 individuals with ADPKD (67% women; age 47 ± 12 years; follow-up 5.2 years [IQR 2.8–9.0]). Three kidney growth patterns were observed: slow progression (24%, <3%/year linear increase), fast progression (39%, ≥3%/year linear increase), and atypical progression (37%, nonlinear growth). Adjusted ht-TKV change in mL/m/year was +1.4 (IQR –4.5 to +10.0), +40.3 (+16.9 to +89.3), and +32.8 (+15.9 to +85.9) for slow, fast, and atypical progressors, respectively (p <0.001). Atypical progressors exhibited a significantly greater decline in eGFR in mL/min/m²/year (–7.9, 95% CI –6.5, –3.9) compared to slow (–0.5, 95% CI –3.1 to +0.5) and fast progressors (–3.4, 95% CI –7.9, –2.0; between-group p <0.001). Atypical progressors had a higher proportion of acute complications, including hemorrhages, infections, and urolithiasis (84%), compared to slow (20%) and fast progressors (31%) (p <0.001). ConclusionIn typical ADPKD, nonlinear, abrupt, and unpredictable cyst growth occurs frequently, leading to a higher risk of acute complications and kidney function decline.

Implications of Proteinuria Remission on Estimated Glomerular Filtration Rate (eGFR) Trajectory in Patients with IgA Nephropathy in the PROTECT Trial

Implications of Proteinuria Remission on Estimated Glomerular Filtration Rate (eGFR) Trajectory in Patients with IgA Nephropathy in the PROTECT Trial

Ten years trajectories of estimated glomerular filtration rate (eGFR) in a multiethnic cohort of people with type 1 diabetes and preserved renal function

ObjectivesWe aim to evaluate estimated glomerular filtration rate (eGFR) patterns of progression in a multiethnic cohort of people with type I diabetes mellitus and with baseline eGFR ≥45 mL/min/1.73 m2.DesignObservational...

Prognosis for Type 1 Diabetes with Diabetic Nephropathy between 2000 and 2020 - Changes in Kidney Function Decline Over Time and Development of Cardiovascular Disease, Kidney Failure, and Mortality

IntroductionIndividuals with type 1 diabetes (T1D) and diabetic nephropathy (DN) experience progressive kidney function decline and high risk of cardiovascular disease (CVD) and mortality. This study explored changes in kidney function decline in new-onset DN between 2000-2020 and provided an updated prognosis for risk of kidney failure, CVD, and mortality. MethodsRegister-based cohort study in T1D with new-onset DN (severely increased albuminuria) between 2000-2020 at Steno Diabetes Center Copenhagen, Denmark. Data was derived from electronic health records and national registers. Kidney function development was expressed as trajectories of estimated glomerular filtration rate (eGFR) and measured GFR (mGFR) using mixed-effects models. The prognosis was presented in probabilities of developing complications, stratified by sex, prior CVD, and risk factor control by using simulations based on Poisson regression analysis. ResultsThe cohort comprised 591 individuals with median (IQR) age at DN onset of 53 (39-66) years and 57% were male. In 283 participants, mGFR were available. Plots of eGFR trajectories illustrated tendencies towards higher eGFR in more recent years, but this was not confirmed in mGFR trajectories. Poor risk factor control, prior CVD and male sex impacted mortality and morbidity rates negatively. For men/women with fair risk factor control and no prior CVD, the 10-year mortality rate from onset of DN was 28/26%. For men/women with poor risk factor control and CVD prior to DN onset, the 10-year-mortality rate was 62/62%. ConclusionThe results do not support an improved prognosis for T1D and DN, emphasizing the urgent need for new therapeutic approaches.

Reduced renal function is associated with faster loss of bone mineral density in patients with non-dialysis CKD

Abstract Background Bone mineral density (BMD) predicts fracture risk in patients with chronic kidney disease (CKD) and in the general population. However, few studies have investigated risk factors for bone loss in patients with CKD. The aim of this study was to investigate whether renal function is associated with the rate of BMD decline. Methods A prospective cohort study included 1 006 patients with CKD stages 2–4 between 2011 and 2016. BMD was measured using dual-energy X-ray absorptiometry at baseline and 4 years. The eGFR was measured 2–6 times during the 4-year follow-up. We analyzed the decline in bone mineral density according to CKD stage and further compared the rate of BMD decline according to eGFR trajectories at each stage. Results Advanced CKD stage was associated with a faster rate of decline in total hip BMD (stage 2: −0.23, stage 3A: −0.39, stage 3B: −0.80, stage 4: −1.23% change/year in men [p &amp;lt; 0.001]; stage 2: −0.86, stage 3A: −1.19, stage 3B: −1.20, stage 4: −1.58% change/year in women [p &amp;lt; 0.03]). Two distinct eGFR trajectories (Class 1: stable group; Class 2: rapid decline group) were observed. The rapid decline group showed a trend toward an increased rate of decline in total hip BMD. Subgroup analysis according to eGFR trajectories revealed a significant difference in BMD decline rate between stable and rapid decline groups. Conclusions Advanced CKD stage and accelerated decline in renal function were associated with rapid BMD decline in non-dialysis patients with CKD.

Prevalence and clinical determinants of rapid eGFR decline among patients with newly diagnosed type 2 diabetes

BackgroundDiabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in the western world. Rapid estimated glomerular filtration rate (eGFR) decline is an independent predictor of ESKD and death in the general population and in subjects with type 2 diabetes mellitus (T2D). AimWe investigated in a large sample of subjects with newly diagnosed T2D the prevalence and clinical determinants of fast eGFR decline, taking advantage from the dataset of the Associazione Medici Diabetologi (AMD) Annals initiative. MethodsThe eGFR trajectories were evaluated by applying a linear mixed model for repeated measures (LMMRM) and rapid eGFR decline defined as an eGFR decline greater than 5 mL/min/1.73 m2 per year at 3 years. ResultsAmong 105,163 (57.7% M) subjects with newly diagnosed T2D, 13,587 (12.9 %) subjects showed a rapid eGFR loss. The independent significant predictors were age, female gender, HbA1c, smoking, high baseline eGFR, albuminuria and retinopathy. ConclusionOur study demonstrates that a significant percentage of newly diagnosed T2D subjects have a rapid eGFR decline. Given the association between dynamic changes in eGFR and the risk of ESKD or death, we suggest to include this variable in the definition of CKD.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Application of the updated International IgA Nephropathy Prediction Tool in children one or two years post-biopsy

The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one-year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two-years after biopsy. Trajectories of eGFR after a baseline one-year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to revaluate risk one- or two-years after biopsy.

An observational cohort study examined the change point of kidney function stabilization in the initial period after transplantation

Baseline kidney function following kidney transplantation is often used in research and clinical decision-making yet is not well defined. Here, a method to determine baseline function was proposed and validated on three single-center retrospective cohorts consisting of 922 patients from Belgium (main cohort) and two validation cohorts of 987 patients from the Netherlands and 519 patients from Germany. For each transplant, a segmented regression model was fitted on the estimated glomerular filtration rate (eGFR) evolution during the first-year post-transplantation. This yielded estimates for change point timing, rate of eGFR change before and after change point and eGFR value at change point, now considered the “baseline function”. Associations of eGFR evolution with recipient/donor characteristics and the graft failure rate were assessed with linear regression and Cox regression respectively. The change point occurred on average at an eGFR value of 43.7±14.6 mL/min/1.73m2, at a median time of 6.5 days post-transplantation. Despite significant associations with several baseline donor-recipient characteristics (particularly, donor type; living vs deceased), the predictive value of these characteristics for eGFR value and timing of the change point was limited. This followed from a large heterogeneity within eGFR trajectories, which in turn indicated that favorable levels of kidney function could be reached despite a suboptimal initial evolution. Segmented regression consistently provided a good fit to early eGFR evolution, and its estimate of the change point can be a useful reference value in future analyses. Thus, our study shows that baseline kidney function after transplantation is heterogeneous and partly related to pretransplant donor characteristics.

Association between chronic intestinal failure etiology and eGFR trajectory in adults receiving home parenteral nutrition: A retrospective longitudinal cohort study.

Patients with chronic intestinal failure (CIF) are at increased risk of developing renal impairment. The aim of this study was to evaluate the occurrence of chronic kidney disease (CKD) in patients dependent on home parenteral nutrition (HPN) and assess risk factors for renal impairment, including patients with all mechanisms of CIF. This was a cohort study of patients initiated on HPN between March 1, 2015, and March 1, 2020, at a national UK IF Reference Centre. Patients were followed from their first discharge with HPN until HPN cessation or the end of follow-up on December 31, 2021. There were 357 patients included in the analysis. Median follow-up time was 4.7 years. At baseline, >40% of patients had renal impairment, with 15.4% fulfilling the criteria for CKD. Mean estimated glomerular filtration rate (eGFR) decreased significantly during the first year after initiation of HPN from 93.32 ml/min/1.73 m2 to 86.30 ml/min/1.73 m2 at the first year of follow-up (P = 0.002), with sequential stabilization of renal function. Increased age at HPN initiation and renal impairment at baseline were associated with decreased eGFR. By the end of follow-up, 6.7% patients developed renal calculi and 26.1% fulfilled the criteria for CKD. This is the largest study of renal function in patients receiving long-term HPN. After the first year following HPN initiation, the rate of decline in eGFR was similar to that expected in the general population. These findings should reassure patients and clinicians that close monitoring of renal function can lead to good outcomes.

The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach.

Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process mining approach. We conducted a retrospective cohort study from 1 January 2006 to 31 December 2011, utilising data from the Stockholm Creatinine Measurements (SCREAM). New users of PPIs and H2 blockers (H2Bs) with CKD (eGFR < 60) were identified using a new-user and active-comparator design. Process mining discovery is a technique that discovers patterns and sequences in events over time, making it suitable for studying longitudinal eGFR trajectories. We used this technique to construct eGFR trajectory models for both PPI and H2B users. Our analysis indicated that PPI users exhibited more complex and rapidly declining eGFR trajectories compared to H2B users, with a 75% increased risk (adjusted hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.49 to 2.06) of transitioning from moderate eGFR stage (G3) to more severe stages (G4 or G5). These findings suggest that PPI use is associated with an increased risk of CKD progression, demonstrating the utility of process mining for longitudinal analysis in epidemiology, leading to an improved understanding of disease progression.

Data driven approach to characterize rapid decline in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease with high phenotypic variability. Furthering insights into patients' ADPKD progression could lead to earlier detection, management, and alter the course to end stage kidney disease (ESKD). We sought to identify patients with rapid decline (RD) in kidney function and to determine clinical factors associated with RD using a data-driven approach. A retrospective cohort study was performed among patients with incident ADPKD (1/1/2002-12/31/2018). Latent class mixed models were used to identify RD patients using differences in eGFR trajectories over time. Predictors of RD were selected based on agreements among feature selection methods, including logistic, regularized, and random forest modeling. The final model was built on the selected predictors and clinically relevant covariates. Among 1,744 patients with incident ADPKD, 125 (7%) were identified as RD. Feature selection included 42 clinical measurements for adaptation with multiple imputations; mean (SD) eGFR was 85.2 (47.3) and 72.9 (34.4) in the RD and non-RD groups, respectively. Multiple imputed datasets identified variables as important features to distinguish RD and non-RD groups with the final prediction model determined as a balance between area under the curve (AUC) and clinical relevance which included 6 predictors: age, sex, hypertension, cerebrovascular disease, hemoglobin, and proteinuria. Results showed 72%-sensitivity, 70%-specificity, 70%-accuracy, and 0.77-AUC in identifying RD. 5-year ESKD rates were 38% and 7% among RD and non-RD groups, respectively. Using real-world routine clinical data among patients with incident ADPKD, we observed that six variables highly predicted RD in kidney function.

The impact of mild and moderate COVID-19 infection on the progression of kidney dysfunction in patients with IgA nephropathy.

Previous research indicates that coronavirus disease 2019 (COVID-19) infection may have a role in triggering immunoglobulin A (IgA) nephropathy. However, limited research has explored the clinical implications of COVID-19 infection in individuals already diagnosed with IgA nephropathy. This study aimed to determine whether COVID-19 infection independently affects the subsequent trajectory of kidney function in IgA nephropathy patients. This was a single-center cohort study. The study included 199 patients diagnosed with IgA nephropathy. The COVID-19 infection status was determined using a combined method: a questionnaire and the Health Code application, both administered at the end of 2022 in northern China. Kidney function trajectory was assessed by the estimated glomerular filtration rate (eGFR), calculated based on serum creatinine levels measured during follow-up outpatient visits. The primary endpoint of interest was the eGFR trajectory. Out of the 199 participants, 75% (n=181) reported a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, determined through antigen or polymerase chain reaction tests, accounting for 79% (n=143) of the infected patients. A significant majority (98%) experienced mild to moderate symptoms. Over a median follow-up period of 10.7months post-COVID-19 infection, notable clinical events included gross hematuria in 30 patients (16.6%), which normalized within an average of 3days. Additionally, a 2-fold increase in proteinuria or progression to the nephrotic range was observed in 10 individuals (5.5%). No cases of acute kidney injury were noted. COVID-19 exposure was associated with an absolute change in eGFR of 2.98mL/min/1.73m2 per month (95% confidence interval 0.46 to 5.50). However, in a fully adjusted model, the estimated changes in eGFR slope post-COVID-19 were -0.39mL/min/1.73m2 per month (95% confidence interval -0.83 to 0.06, P=.088) which included the possibility of no significant effect. Notably, a higher rate of kidney function decline was primarily observed in patients with a baseline eGFR <45mL/min/1.73m2 [-0.56mL/min/1.73m2 (-1.11 to -0.01), P=.048]. In the cohort, there were few instances of severe COVID-19 cases. The absence of long-term follow-up outcomes was observed. Overall, mild to moderate COVID-19 infection does not appear to significantly exacerbate the subsequent decline in kidney function among IgA nephropathy patients, particularly in those with preserved baseline kidney function.

The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC)

The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC)

Bortezomib for antibody-mediated rejection of kidney transplant in youth: Associations with donor-specific antibody.

Antibody-mediated rejection is one of the most significant risk factors for allograft dysfunction and failure in children and adolescents with kidney transplants, yet optimal treatment remains unidentified. To date, there are mixed findings regarding the use of Bortezomib, a plasma cell apoptosis inducer, as an adjunct therapy in the treatment of antibody-mediated rejection. In a retrospective single center study, we reviewed the efficacy and tolerability of bortezomib as adjunct therapy for treatment-refractory antibody-mediated rejection. Six patients with a median age of 14.6 years (range 6.9-20.1 years) received bortezomib at a mean of 71 months (range 15-83 months) post-kidney transplant. Four patients experienced decline in estimated glomerular filtration rate (eGFR) from 4% to 42%. One patient started bortezomib while on hemodialysis and did not recover graft function, and another patient progressed to hemodialysis 6 months after receiving bortezomib. Although DSA did not completely resolve, there was a statistically significant decline in DSA MFI pre and 12-months post-BZ (p = .012, paired t-test) for the subjects who were not on dialysis at the time of bortezomib. Chronic Allograft Damage Index (CADI) score of ≥3 was seen in all six subjects at their biopsy prior to therapy. No adverse effects were reported. Bortezomib was well tolerated and resulted in improvements in MFI of DSA among four pediatric subjects without allograft failure, although no effects were observed on eGFR trajectory. Further studies are needed to clarify whether earlier intervention with bortezomib could prevent renal failure progression.

Bone health in young adults with type 1 diabetes and progressive eGFR decline

BackgroundType 1 Diabetes (T1D) is associated with increased risk of fractures, worsened by presence of microvascular complications. This study’s objective is to determine the impact of progressive decline in estimated glomerular filtration rate (eGFR) on bone biomarkers and bone microarchitecture in youth with T1D.MethodsSlopes of eGFR were calculated using measures obtained at four timepoints from adolescence to young adulthood. Participants were identified as eGFR decliners if eGFR decreased ≥ 3ml/min/1.73m2/year. Bone health was assessed in young adulthood by high resolution peripheral quantitative computed tomography (HRpQCT Xtreme CTII) and bone biomarkers; osteocalcin, procollagen 1 intact n-terminal pro-peptide (P1NP), c-terminal telopeptide (CTX), and bone specific alkaline phosphatase. The relationship between diabetes duration, glycated hemoglobin, body mass index (BMI) and vitamin D level on bone biomarkers and microarchitecture was evaluated. Linear regression analysis was used for the statistical analysis in this study.ResultsNinety-nine study participants were studied with longitudinal evaluation of eGFR over 7.4 ± 1.0 years with mean age of 14.7 ± 1.7 years at baseline. Cross sectional evaluation of bone was performed at 21.3 ± 2.1 years. 44% participants had eGFR decline and showed 5% higher cortical porosity diameter than non-decliners (p = 0.035). Greater diabetes duration was associated with higher trabecular separation (p = 0.004) and lower trabecular number (p = 0.01). Higher level of 25 hydroxy-vitamin D was associated with lower trabecular separation (p = 0.01). Elevated glycated hemoglobin (p = 0.0008) and BMI (p = 0.009), were associated with lower markers of bone formation.ConclusionMild increase in cortical porosity diameter was found in youth with T1D and eGFR decline, however, overall measures of bone microarchitecture on HR-pQCT were similar between both groups and there were no statistically significant changes in bone biomarkers. Hence, skeletal impairments were limited in youth with different eGFR trajectories near peak bone mass. Longitudinal HR-pQCT studies are needed to further understand the impact of eGFR decline on bone microarchitecture. Optimal glycemic control, normal BMI and vitamin D status were supported by this study as important markers for good bone health.

#2638 SGLT2i in CKD with high albuminuria: an observational real-world study

Abstract Background and Aims Dapagliflozin, a sodium–glucose co-transporter-2 inhibitor (SGLT2i), is indicated to treat chronic kidney disease (CKD). Clinical trials have shown that dapagliflozin significantly reduces albuminuria in patients with urine albumin-creatinine ratio (UACR) 200–5000 mg/g and has beneficial effects on estimated glomerular filtration rate (eGFR) decline and combined kidney outcomes. In the DAPA-CKD trial, dapagliflozin led to substantial reductions in the composite of sustained eGFR decline of ≥50%, end-stage kidney disease, and renal or cardiovascular death (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.51, 0.72; p &amp;lt; 0.001), with similar reductions observed across UACR subgroups. Furthermore, compared with placebo, dapagliflozin reduced geometric mean UACR by 29.3% (95% CI: –33.1, –25.2; p &amp;lt; 0.0001), with no difference in relative UACR reduction by baseline UACR above or below 1000 mg/g. In the ZENITH-CKD study, over 12 weeks the combination of zibotentan (a novel endothelin A receptor antagonist) and dapagliflozin showed a robust reduction in UACR of 47.7% vs 28.3% for dapagliflozin alone, with this effect maintained in patients with UACR &amp;gt;700 mg/g. It is well known that renal disease progresses more quickly in patients with higher degree of albuminuria than in those with lower levels. We aimed to further characterize renal risk in patients with different levels of residual albuminuria despite standard of care treatment with renin–angiotensin system inhibitors (RASi) and SGLT2i. Methods We used a large USA claims database (Optum's de-identified Clinformatics® Data Mart Database [CDM]) to identify patients aged ≥18 years with CKD, defined as either two eGFR measurements ≤60 mL/min/1.73 m2 taken ≥90 days apart or a first eGFR ≤60 mL/min/1.73 m2 and a CKD diagnosis. Patients were indexed at the date of dapagliflozin 10 mg initiation between 30 April 2021 (date of approval for dapagliflozin in CKD) and March 2023. Patients with prior use of SGLT2i, immunosuppressive drugs, hydroxychloroquine, CKD stage 5 (based on eGFR &amp;lt;15 mL/min/1.73 m2 or dialysis), polycystic kidney disease, or type 1 or gestational diabetes were excluded. Patients were indexed on 1st January 2022 and grouped into two UACR groups: ≥700UACR group (≥700 mg/g) and &amp;lt;700UACR group (200–699 mg/g). Outcomes were UACR changes, eGFR slopes and CKD-associated hospitalizations within 1 year after dapagliflozin initiation. Hazard ratios were estimated using adjusted Cox survival regression. UACR follow-up analyses were restricted to patients with at least one follow-up measurement. Results In the 5908 patients with CKD, median UACRs at index in the ≥700UACR and &amp;lt;700UACR groups were 1414 mg/g and 102 mg/g, respectively. Patients in the ≥700UACR group vs &amp;lt;700UACR group had lower eGFR (40 vs 48 mL/min/1.73 m2), were younger (71 vs 74 years), and both groups had a high burden of comorbidities (heart failure: 38% vs 42%; type 2 diabetes: 74% vs 75%). RASi use was 81% and 74%, respectively. During follow-up, 22% of patients in the ≥700UACR group experienced a CKD-related hospitalization (25.1 events per 100 patient years) as compared to 19.5 events per 100 patient years in the &amp;lt;700UACR group (HR 1.38 [95% CI: 1.16, 1.64, p &amp;lt; 0.001]; Fig. panel A). The eGFR slope (95% Cl) of patients in the ≥700UACR group was –2.44 mL/min/1.73 m2 per year (–3.49, –1.65), compared with a flat eGFR trajectory in patients in the &amp;lt;700UACR group (0.39 [–0.11, 0.96]). In the ≥700UACR group with at least one follow-up measurement (n = 431), UACR lowered from 2077 mg/g to 1674 mg/g (–36.3%) within 1 month of dapagliflozin initiation but remained above 1200 mg/g throughout the 12-month follow-up period (Fig. panel B). Conclusions While treatment with RASi and SGLT2i are associated with reduced risk of renal outcomes in patients with CKD, awareness and management of residual albuminuria remains an area of unmet clinical need. The novel combination of zibotentan/dapagliflozin currently under investigation in the ZENITH High Proteinuria phase III trial (NCT06087835) seeks to address this need.

Association of Estimated Glomerular Filtration Rate Trajectories with Atrial Fibrillation Risk in Populations with Normal or Mildly Impaired Renal Function

Plain Language SummaryThe relation between estimated glomerular filtration rate (eGFR) within the normal or mildly impaired range and risk of atrial fibrillation (AF) in former studies is controversial, and data on longitudinal pattern of eGFR in such topic is sparse. In this cohort study, we identified 4 trajectories of eGFR in populations with normal or mildly impaired renal function. Relative to populations with high-stable pattern of eGFR, those with low-stable pattern, high-decreasing pattern and moderate-increasing pattern were associated with 128%, 92%, and 70% higher risk of AF, respectively. These findings suggested that monitoring eGFR trajectories is an important approach for AF prediction in populations with normal or mildly impaired renal function. Decreasing and consistently low eGFR trajectories within the currently designated normal or mildly impaired range may still significantly increase the risk of AF.

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.

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. 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. 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). 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.