Background There is no consensus on the optimal metric for long-term tacrolimus monitoring after kidney transplantation. It remains unknown how tacrolimus exposure changes over time and how tacrolimus monitoring metrics are related to long-term outcomes. Methods We examined tacrolimus exposure beyond the first year after kidney transplantation, as assessed by multiple monitoring metrics (i.e., mean trough level, intra-patient variability [IPV], time in therapeutic range [TTR], time below range, time above range), in the Wisconsin Allograft Recipient Database. We examined associations of these metrics with late graft outcomes (late rejection, uncensored and death-censored graft failure [DCGF]) and mortality (death with a functioning graft [DWFG]). Results A total of 1994 kidney transplant recipients, who received tacrolimus-based immunosuppression and survived at least 12 months with a functioning graft, were included. We observed a decreasing trend of tacrolimus exposure over median follow-up of 5.3 years. A high tacrolimus IPV (coefficient of variation ≥30%) in the second year was most strongly associated with outcomes, including a 45% higher risk of uncensored graft failure (adjusted hazard ratio =1.45; 95% confidence interval: 1.22, 1.72; p <0.01). A higher IPV also was associated with a higher risk of death-censored graft failure, mortality, and late rejection. Cumulative high tacrolimus IPV in the past 5 years was associated with higher risk of graft failure and mortality. Conclusion Metrics of tacrolimus exposure assessed beyond the first year after kidney transplantation, especially IPV, remain informative for long-term outcomes.
INTRODUCTION:The clinician-identified barriers to person-centered chronic kidney disease (CKD) care remain poorly characterized among socioeconomically disadvantaged populations. We examined nephrology clinicians' perspectives on patient preparation, dialysis decision-making, and structural barriers to inform multilevel intervention. METHODS:A qualitative descriptive study using semi-structured interviews and thematic analysis following Braun and Clarke's (2006) approach [29] included 22 English-speaking nephrology clinicians recruited via snowball sampling. Transcripts were analyzed thematically. RESULTS:Three themes emerged. First, CKD awareness, education, and preparedness: patient awareness was uneven and often absent even under nephrology care; education was multidisciplinary and stage-sensitive but emotionally constrained. Second, dialysis decision-making: planned outpatient initiation was distinguished from unplanned emergency starts, the latter associated with reduced patient choice and worse outcomes; modality discussions typically began at an estimated glomerular filtration rate (eGFR) of approximately 20 mL/min/1.73m² but timing varied widely; nephrology clinicians sometimes omitted home dialysis options when patient support seemed uncertain; and family involvement was central to adherence and decision quality. Third, barriers, supports, and clinical management: nonadherence reflected structural barriers, financial hardship, health literacy, transportation, and delayed referral, rather than motivation, while the clinician-patient relationship was a modifiable adherence determinant limited by understaffed support services. DISCUSSION:Nephrology clinicians identified patient awareness, education timing, provider variability, and structural barriers as modifiable determinants of inequitable CKD outcomes. Multilevel intervention targeting pre-dialysis education, primary care coordination, reimbursement reform, and social support infrastructure is needed.
BACKGROUND:Adynamic bone disease (ABD) is an increasingly prevalent form of low-turnover renal osteodystrophy in advanced chronic kidney disease (CKD). ABD was not recognized as a clinical entity prior to the widespread adoption of PTH-targeted therapeutic strategies, and sustained iatrogenic suppression of parathyroid hormone (PTH) activity is now understood as the primary and defining causal mechanism underlying the adynamic phenotype. Uremic toxins, FGF-23-Klotho dysregulation, impaired vitamin D signaling, chronic inflammation, calcium-phosphate imbalance, and osteocyte-mediated abnormalities function as modulatory contributors that amplify skeletal susceptibility within the context of sustained PTH suppression, rather than independent drivers of ABD. Clinically, ABD is associated with impaired bone quality, increased fracture risk, vascular calcification, and musculoskeletal frailty, abnormalities that are often not adequately reflected by areal bone mineral density measurements alone. SUMMARY:ABD in advanced CKD represents a PTH suppression-driven skeletal remodeling phenotype characterized by osteoblast, osteoclast, and osteocyte dysfunction together with disruption of osteoblast-osteoclast coupling. Suppression of Wnt/β-catenin signaling, elevated sclerostin expression, impaired mechanotransduction, skeletal resistance to PTH, and accumulation of uremic toxins collectively contribute to globally reduced remodeling activity and defective microdamage repair. In the context of markedly suppressed bone turnover, antiresorptive therapy is biologically unlikely to confer skeletal benefit and may exacerbate impairment of bone remodeling and renewal. By contrast, anabolic strategies aimed at restoring PTH1R-dependent bone formation and remodeling activation are mechanistically appropriate in CKD-associated ABD. Current evidence suggests that intermittent PTH analog therapy, particularly teriparatide, may improve bone formation markers, bone mineral density, and remodeling activity in selected CKD patients with low-turnover bone disease. Abaloparatide is mechanistically promising but clinically unvalidated in advanced CKD. Romosozumab should not be used in clinical practice for CKD-associated ABD given profound uncertainties regarding cardiovascular safety, vascular calcification, and calcium handling in this population. Practical considerations regarding patient selection, biochemical monitoring, prevention of ABD through avoidance of prolonged PTH suppression, and individualized treatment strategies are also discussed.
INTRODUCTION:Chronic kidney disease (CKD) disproportionately burdens non-Hispanic Black (NHB) patients who experience a three- to four-fold higher risk of kidney failure than non-Hispanic White (NHW) individuals. Diabetes and hypertension are the leading causes of CKD, yet the influence of race, social context, and clinical factors on major adverse kidney events (MAKE) remains inadequately understood. This study examined relationships between race, social factors, and MAKE among patients with diabetes or hypertension. METHODS:Electronic health record data from the CURE-CKD Registry (2013-2022) were used to assemble two mutually-exclusive cohorts of NHB and NHW (reference) adults with 1. diabetes (N=375,605) or 2. Hypertension without diabetes (N=710,768). The primary outcome was time to first MAKE, defined as ≥40% decline in estimated glomerular filtration rate (eGFR), eGFR <15 mL/min/1.73 m², kidney failure, dialysis, transplant, or death. Cox proportional hazards models estimated associations between predictors and MAKE. Extreme gradient boosting (XGBoost) machine learning (ML) models were used as a complement to the traditional survival models to evaluate variable relationships with MAKE and compare predictive performance. RESULTS:NHB patients were younger (diabetes: 56±15 vs. 62±14 years; hypertension: 50±16 vs. 59±16 years), had more prevalent CKD (diabetes: 19% vs. 15%; hypertension: 8% vs. 7%), and had higher adjusted MAKE risk than NHW patients (diabetes: HR=1.07, 95% CI: 1.04-1.11; hypertension: HR=1.10, 95% CI: 1.06-1.14). MAKE occurred in 24% (n=90,910) of the diabetes population over a median (interquartile range) of 4.1 (2.0-6.3) years, and 15% (n=106,209) of the hypertension population over 4.4 (2.4-6.3) years. Non-commercial insurance (Medicaid, Medicare or unclassified insurance [reference: Commercial]), higher social vulnerability index, more frequent hospitalizations, and urban residence were the top predictors of MAKE. XGBoost outperformed Cox models for MAKE prediction and SHapley Additive exPlanations value rankings confirmed key predictors identified in Cox models. CONCLUSION:Across two large cohorts at-risk for CKD, NHB patients experienced higher MAKE risk, shaped by neighborhood social and structural conditions rather than demographic and clinical characteristics alone. Integrating social risk assessment, improving guideline-directed testing, and using complementary ML and Cox modeling approaches may enhance early identification of CKD risk, support targeted intervention, and reduce disparities in CKD outcomes.
Introduction Diabetic kidney disease (DKD) is characterized by impairment of renal glomerular and tubular cells. Low plasma levels of ceramides and lactosylceramides containing very long-chain (VLC) fatty acid were found to be predictive of DKD development. Elongase 1 (Elovl1) is a ubiquitous elongase that elongates C20-C22 fatty acids to generate very long-chain C24 fatty acids. Using a novel transgenic mouse overexpressing Elovl1, we investigated whether modification to sphingolipid fatty acid composition averts DKD development. Methods A transgenic (TG) mouse overexpressing Elovl1 was created at the Medical University of South Carolina/Transgenic Core. Elovl1 TG and wild type (WT) mice were rendered diabetic using serial streptozotocin injections. Plasma, kidney, liver, and urine sphingolipidomics of diabetic and non-diabetic TG and WT mice were analyzed using mass spectroscopy and Matrix-Assisted Laser Desorption/Ionization-Imaging Mass Spectrometry. Sphingolipid metabolizing enzymes were analyzed using immunohistochemical & multispectral imaging coupled with digital analysis. Results Plasma sphingomyelins were higher, but lactosylceramides were lower in diabetic TG than in diabetic WT mice. Kidney lactosylceramides were also lower in diabetic TG mice. In urine, diabetic TG mice excreted more VLC lactosylceramides than diabetic WT mice, but less VLC sphingomyelins, VLC ceramides, sphingosine and sphingosine 1-phosphate. There was extensive damage to proximal tubules in kidneys of diabetic WT mice compared to diabetic TG mice. Glomeruli in diabetic WT kidneys appeared also abnormal, whereas no obvious abnormality of glomeruli in diabetic TG was observed. In diabetic TG, Elovl1 overexpression resulted in decreased kidneys levels of both ceramide synthase and acid sphingomyelinase, but increased acid ceramidase levels compared to non-diabetic TG mice. Conclusion The diabetic Elovl1 TG mouse revealed interaction between Elovl1 overexpression and DKD development, and showed that distinct VLC sphingolipids could be involved in maintaining cell membrane integrity of renal cells.
INTRODUCTION:Hyperkalemia is a life-threatening disorder in chronic kidney disease (CKD), yet the contribution of key factors including age, sex, body mass index and proteinuria remain controversial. We aimed to identify factors associated with chronic hyperkalemia in a large cohort of patients with gold-standard measured glomerular filtration rate (GFR) and standardized plasma potassium measurements. METHODS:This cross-sectional study of 5046 adults with non-dialysis CKD referred for kidney workup, including radio-isotopic measured GFR, defined hyperkalemia as a plasma potassium concentration ≥5.0 mmol/L or the use of potassium binders. We analyzed demographic, clinical, pharmacological and biochemical risk factors for hyperkalemia using logistic regression models. RESULTS:Mean measured GFR was 59±26 mL/min/1.73 m2, mean age was 52±15 years, 42% were women, 22% of sub-Saharan African ancestry, 25% had diabetes, and 36% were kidney transplant recipients. The prevalence of hyperkalemia was 6.4% and increased with declining measured GFR, from 1% in CKD stages 1-2 to 8% in CKD stage 3 and 21% in stages 4-5. In the multivariable model, measured GFR remained strongly associated with hyperkalemia (OR 1.65 [1.51-1.81] per 10 mL/min/1.73m² decrease), an effect amplified in renin-angiotensin-aldosterone system inhibitor (RAASi) users (1.82 [1.61-2.07]) (p for interaction 0.036). Other independently associated factors were diabetes (OR 1.67 [1.38-2.17]), RAASi and calcineurin inhibitors (OR 2.30 [1.72-3.11] and 1.39 [1.06-1.83] respectively), higher urinary albumin-to-creatinine ratio and lower venous bicarbonate level, whereas female sex (OR 0.71 [0.55-0.92]), sub-Saharan African ancestry (HR 0.68 [0.48-0.94]), and loop-diuretics (OR 0.71 [0.51-0.98]) were protective, and age and body mass index showed no independent association. CONCLUSION:In this large cohort, across the entire range of gold-standard measured GFR, hyperkalemia is driven primarily by reduced kidney function, diabetes, and RAASi, whereas protective factors were female sex, sub-Saharan African ancestry, and loop diuretic therapy. These robust findings, based on unbiased GFR assessment, identify key contributors for individualized prevention of hyperkalemia in CKD.
We thank Gao and Lu for their thoughtful comments on our study investigating the association between sodium-glucose cotransporter-2 inhibitor (SGLT-2i) use and acute kidney injury (AKI) risk in hospitalised patients. In this reply, we clarify several methodological and interpretative aspects of our study. In particular, secondary analyses of continuation, discontinuation and initiation of SGLT-2i during hospitalisation should be interpreted cautiously, as these treatment decisions are likely influenced by clinical stability and other unmeasured factors. We further address concerns regarding AKI ascertainment, baseline creatinine selection, indication-stratified analyses, and the limited feasibility of dose- or agent-specific comparisons. Additional sensitivity analyses did not suggest major imbalance in early AKI detection between groups. Overall, we agree that the findings of our secondary analysis should be considered hypothesis-generating rather than definitive evidence for inpatient continuation of SGLT-2i. Future studies using prospective designs, time-updated exposure modelling or target trial emulation are needed to determine which patients may safely benefit from continuation during hospitalisation.
INTRODUCTION:Lower estimated glomerular filtration rate (eGFR) is associated with worse clinical outcomes in people with heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fractions. Data on the association of functional exercise capacity and patient-reported outcomes in HF with eGFR measures using Cr (eGFRcr) are conflicted and scarce using cystatin C (eGFRcys). METHODS:We evaluated the association between baseline eGFR and scores on 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) at baseline and 6 months in 769 participants from EXACT-HF, RELAX, and FIGHT trials. eGFR measures were eGFRcr, eGFRcys, a combination (eGFRcr-cys), and discordance in eGFR (eGFRcys at least 30% lower than eGFRcr, i.e. eGFRcys/GFRcr<0.7). Multivariable linear regression adjusted for age, sex, diabetes, BMI, NYHA class, NT-proBNP, and treatment arm. RESULTS:Median eGFRcr was 54 [40, 74], eGFRcys 49 [34, 70], and eGFRcr-cys 54 [38, 72] ml/min/1.73m2. eGFRcys/eGFRcr was <0.7 in 20%. Lower eGFR using all measures was associated with 6MWT at baseline. Only cystatin C-derived measures were associated with 6MWT at 6 months in adjusted models: eGFRcys, β (95% CI), 8.7 (4.1, 13.4), p<0.001; eGFRcr-cys, 7.7 (3.0, 12.5), p=0.001; per 10 ml/min/1.73m2 increase in eGFR). Discordance in eGFR was associated with a 34.9 (10.4, 59.4) meter drop in distance walked at 6 months (p=0.005). Only cystatin C-derived eGFR measures were associated with KCCQ at 6 months (eGFRcys/eGFRcr <0.7: 7.8 (-13.9, -1.7), p=0.01; eGFRcys: 1.9 (0.9, 2.9), p<0.001; eGFRcr-cys: 1.7 (0.6, 2.8), p=0.003; per 10 ml/min/1.73m2 increase in eGFR). Only eGFRcys/eGFRcr was associated with an improvement in MLHFQ score on fully adjusted analysis. CONCLUSION:Lower eGFR measures using cystatin C but not creatinine predicted worse performance at 6 months on functional and patient-reported outcomes in people with HF. These findings highlight the prognostic importance of cystatin C-based eGFR measures in HF.
INTRODUCTION:NT-proBNP is a critical biomarker in the management of heart failure. However, its role in tracking cardiovascular (CV) function and structure in patients with advanced chronic kidney disease (CKD) and after kidney transplantation remains unclear. Herein, we investigated the association between NT-proBNP with CV function and structure in advanced CKD and longitudinally post-kidney transplantation. METHODS:We assessed 159 stage 5 CKD patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, including kidney transplant recipients (KTRs) and waitlisted controls (NTWCs). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline and 1-year follow-up and were stratified by baseline NT-proBNP quartiles (Q1-Q4). RESULTS:Groups were balanced by sex and race (p > 0.05); however, Q4 patients were older, had lower BMI, and were predominantly on hemodialysis (all p < 0.03). Higher baseline NT-proBNP was associated with lower VO2Max (gold-standard index of CV functional capacity), reduced peak HR, workload, endurance time, and elevated LVMI (all p < 0.007). Longitudinally, NTWCs demonstrated worsening VO2Max, workload, peak HR, and endurance time, along with a mean 89% increase in NT-proBNP. In KTRs, VO2Max, workload, and endurance time improved in parallel with a mean 92% reduction in NT-proBNP after transplantation (all p ≤ 0.02). Changes in logNT-proBNP before and after transplantation were associated with alterations in VO2Max, peak HR, workload, and elevated LVMI (all p < 0.02). CONCLUSION:Elevated NT-proBNP reflects impaired CV function and structure in advanced CKD and may serve as a prognostic biomarker for tracking improvements in CV health in patients with advanced CKD and undergoing kidney transplantation.
INTRODUCTION:The lead time needed for vascular access (VA) creation before hemodialysis (HD) initiation remains unclear. Because arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) differ in expected time to cannulation, the association between VA timing and outcomes may differ by access type. METHODS:Using the Korean National Health Insurance Service database, we identified incident HD patients in 2013 who underwent AVF or AVG creation before HD initiation. Patients were classified according to the interval from VA creation to HD initiation: VA0 (<1 month), VA1 (1 to <3 months), VA3 (3 to <6 months), VA6 (6 to <9 months, reference), VA9 (9 to <12 months), and VA12 (12 to ≤24 months). Catheter use, patency loss, and mortality were analyzed separately in AVF and AVG patients using logistic regression, Kaplan-Meier analysis, and Cox models. RESULTS:Among 24,713 patients, 20,894 underwent AVF and 3,819 underwent AVG creation. In AVF patients, compared with VA6, VA0, and VA1 were associated with higher catheter use (odds ratios, 14.03 and 1.85), primary patency loss (hazard ratios [HRs], 2.64 and 1.16), secondary patency loss (HRs, 4.56 and 1.12), and mortality (HRs, 1.67 and 1.25). In AVG patients, adverse associations were mainly observed in VA0, including higher catheter use (odds ratio, 8.45), primary patency loss (HR, 1.97), secondary patency loss (HR, 2.06), and mortality (HR, 1.43). Primary patency loss was also higher in VA1. CONCLUSION:The association between VA creation timing and outcomes differed between AVF and AVG. For AVF, creation at least 3 months before HD initiation was associated with more favorable outcomes. For AVG, adverse associations for most outcomes were concentrated within 1 month before HD initiation.
INTRODUCTION:Decreased erythropoiesis-stimulating agent (ESA) requirements might explain the benefits of high-dose intravenous (IV) iron in PIVOTAL. However, as iron can be beneficial via non-erythropoietic pathways, higher iron doses might relate to better outcomes independently of ESA doses. This post hoc analysis examines whether reductions in ESA exposure were associated with the benefits of IV iron, and whether IV iron doses remained associated with outcomes after accounting for ESA exposure and haemoglobin (Hb) levels in PIVOTAL. METHODS:We analysed data from 2,141 participants in the PIVOTAL trial. Primary endpoint was all-cause mortality (ACM) or nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. RESULTS:Baseline median (IQR) ESA dose was 8,000 (5,000, 10,000) IU/week and similar in both treatment arms. Over 24 (10, 33) months, 658 (31%) patients met the primary endpoint, and ACM occurred in 515 (24%) patients. In adjusted Cox models, higher baseline ESA doses (per 10,000 IU/week) were associated with increased risks (primary endpoint: HR: 1.31 [95% confidence interval [CI]: 1.16, 1.49], p < 0.001; ACM: HR: 1.33 [95% CI: 1.15, 1.53], p < 0.001) in reactive patients. Over time, proactive patients had lower ESA (25,980 [17,320, 43,300] vs. 34,640 [25,980, 56,290] IU/month) and higher iron (250 [193, 300] vs. 127 [88, 171] mg/month) doses. In adjusted Cox models with time-varying covariates, higher ESA doses (≥34,640 IU/month) were associated with increased risks (primary endpoint: HR: 1.58 [95% CI: 1.34, 1.86], p < 0.001; ACM: HR: 1.83 [95% CI: 1.51, 2.20], p < 0.001), while higher iron doses (≥200 mg/month) were linked to reduced risks (primary endpoint: HR: 0.78 [95% CI: 0.67, 0.92], p = 0.002; ACM: HR: 0.78 [0.65, 0.93], p = 0.001) in the total population. CONCLUSION:Lower ESA requirements predicted better outcomes in PIVOTAL, but higher IV iron doses remained associated with better outcomes even after accounting for ESA dose requirements and Hb levels. These findings suggest that some of the benefits of proactive IV iron in PIVOTAL may not be fully mediated by reductions in ESA exposure alone, supporting the possibility of non-erythropoietic mechanisms.
INTRODUCTION:Metabolic syndrome is a potent risk factor for adverse cardiovascular outcomes including atrial fibrillation (AF). Although metabolic syndrome is common among patients with chronic kidney disease (CKD), its association with AF remains unclear. METHODS:We analyzed 4,641 participants in the Chronic Renal Insufficiency Cohort (CRIC) without baseline AF. Cox regression models evaluated the association of a metabolic syndrome score (Adult Treatment Panel III criteria), its components (hypertension, diabetes, waist circumference, elevated triglycerides, low HDL), and markers of visceral adiposity (waist-to-height ratio and fat mass index) with time to hospitalization with AF. The main model adjusted for demographics, stroke, lifestyle factors (smoking, alcohol use), and whether participants had ever been seen by a nephrologist (as a marker of healthcare utilization). An exploratory model additionally adjusted for laboratory parameters (eGFR, proteinuria, hemoglobin, albumin, and electrolytes), other cardiovascular comorbidities, and medications. RESULTS:The mean age of the participants was 59 ± 11 years, and 44% were female and 42% were black. Over a mean follow-up of 9.3 years, 616 (13%) were hospitalized with AF. Higher metabolic syndrome score was associated with hospitalization with AF (adjusted hazard ratio (aHR) per unit 1.16; 95% CI 1.08, 1.24). Elevated waist circumference and hypertension were the most consistently associated individual components, remaining independently associated with hospitalization with AF across all models including with concomitant adjustment for the remaining metabolic syndrome components (aHR 1.29; 95% CI 1.05, 1.60 and aHR 1.61; 95% CI 1.09, 2.39, respectively). The waist-to-height ratio and fat mass index were also associated with hospitalization with AF in the main adjusted model (aHR per 0.1 unit, 1.23; 95% CI, 1.14, 1.34 and aHR per 5 kg/m2, 1.22; 95% CI, 1.12, 1.34, respectively). CONCLUSION:Among adults with CKD and no prior AF, hypertension and anthropometric markers of visceral adiposity are independently associated with a higher risk of hospitalization with AF. Future studies should explore mechanisms linking body composition to arrhythmia in CKD and whether reducing visceral adiposity could mitigate this risk.
INTRODUCTION:There is a great burden of cerebral small-vessel disease (CSVD) in dialysis population. Arterial stiffness, normally assessed by pulse-wave velocity (PWV), is an important risk factor for CSVD. We aimed to investigate the effect of PWV on CSVD and related consequences, including cognitive function, cardiovascular disease (CVD), and mortality in dialysis. METHODS:In a prospective cohort of maintenance dialysis adults, 3 features of CSVD including cerebral microbleed (CMB), lacunae, and white matter hyperintensity (WMH) were measured. PWV was assessed by sequential recording of electrocardiogram-gated carotid and femoral artery pressure waves. The effect of PWV on CSVD and cognitive impairment were investigated by multivariate regression analysis. Cox proportional hazards model was used to assess the risk of CVD and mortality up to 10 years follow-up. RESULTS:In the 178 study subjects, the frequency of CMB, lacunae, and WMH was 32.6%, 25.3%, and 34.8%. PWV was related to the risk of lacunae in subcortical white matter (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.02-1.20) and WMH (OR, 1.11; 95% CI, 1.02-1.20) in crude analyses. Unadjusted associations between PWV and cognitive impairment, which were reflected in loss of global function, verbal memory, and executive function, were also detected. At follow-up, PWV was associated with CVD (hazard ratio [HR], 1.13; 95% CI, 1.08-1.18) and all-cause mortality (HR, 1.11; 95% CI, 1.06-1.16) after confounder adjustment. Restricted cubic splines depicted a linear relationship between PWV and the outcome events. CONCLUSION:PWV was associated with all-cause mortality and CVD, independent of age and sex. PWV was associated with CVSD and cognitive decline in unadjusted analyses. PWV is a widely available measurement and could be an early biomarker and provide predictive value in this population.
INTRODUCTION:The Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial compared the effects of cinacalcet against placebo on major cardiovascular events in 3,883 hemodialysis patients with secondary hyperparathyroidism. In this manuscript, we describe heart failure events in EVOLVE and the role of centralized adjudication on heart failure reporting. METHODS:A central clinical events classification committee (CEC) defined and adjudicated suspected heart failure events reported by the site investigators. The treatment effect was analyzed by intention to treat. RESULTS:Overall, 3,883 participants were enrolled, 1,366 heart failure events were reported by site investigators, and 40 potential events were identified independently by the CEC. Among site investigator-reported events, 653 (47.8%) were adjudicated by the CEC as heart failure endpoints. Of the 40 potential events identified independently by the CEC, 17 (42.5%) were adjudicated as heart failure endpoints. The effect of cinacalcet compared with placebo on time to first heart failure event using CEC-adjudicated and site investigator-reported events (10.6% and 12.2% for CEC-adjudicated events [relative hazard 0.82, 95% CI: 0.68-0.99] and 20.3% and 22.1% for site investigator-reported events [relative hazard 0.88, 95% CI: 0.77-1.01]) was similar, although CEC data included fewer events but nominally statistically significant results. CONCLUSION:Roughly half of heart failure events reported by site investigators were not adjudicated as heart failure by the CEC. Site investigators failed to report additional events that were later adjudicated as heart failure endpoints. These findings suggest that, in the hemodialysis population, identifying and classifying heart failure events is challenging and highlight the importance of centralized adjudication to ensure specificity and consistency in clinical events ascertainment.
INTRODUCTION:Patients with nonselective proteinuria generally have a worse prognosis than those with selective proteinuria. However, this has never been studied in kidney transplant recipients (KTRs). This study aimed to evaluate the association between proteinuria selectivity and graft failure among KTRs. METHODS:We used data from KTRs with a functioning graft ≥1 year after transplantation who enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study and had urinary albumin excretion ≥30 mg/24-h and urinary protein excretion >150 mg/24-h. The selectivity of proteinuria was based on the clearance ratio of IgG to albumin (≤0.10 = highly selective; >0.10 = moderate/nonselective). Multivariable Cox regression analyses were performed to evaluate the association between proteinuria selectivity and graft failure. RESULTS:A total of 335 KTRs (36% female, median 6 years after transplantation, mean estimated glomerular filtration rate [eGFR] 47 mL/min/1.73 m2) were included in the analyses. Of them, 107 (31.9%) had moderate/nonselective proteinuria. KTRs with moderate/nonselective proteinuria had lower eGFR, higher 24-h urinary protein excretion, and higher levels of tubular injury markers. During a median follow-up of 5.2 years after baseline measurement, 66 (19.7%) KTRs developed death-censored graft failure. Moderate/nonselective proteinuria was significantly associated with a higher risk of graft failure, independent of potential confounders, including eGFR and 24-h urinary protein excretion (adjusted hazard ratio [95% confidence interval] = 2.10 [1.12-3.94], p = 0.020). CONCLUSION:The independent association between proteinuria selectivity and graft failure highlights the importance of evaluating proteinuria selectivity, in addition to urinary protein, in routine clinical care for KTRs.
INTRODUCTION:Low muscle mass and increased visceral fat are associated with increased mortality and adverse health outcomes, but measurement of components of body composition is not routine. The creatinine muscle index (CMI) has been described as a novel surrogate marker for muscle mass. The waist-to-hip ratio (WHR) is a recognised surrogate marker for visceral adiposity. We sought to study the associations of CMI and WHR with survival, cardiovascular events, and chronic kidney disease (CKD) progression. METHODS:This was a prospective observational cohort study of 1,732 people with CKD category G3 and followed up for 5 years. The primary outcomes were time to cardiovascular events and all-cause mortality over a 5-year period, and secondary outcome was progression of CKD. RESULTS:Participants in the higher tertiles of CMI were younger, more likely to be male, and had higher serum albumin, lower BMI, and lower WHR. Two hundred forty-eight participants (14.3%) died prior to their visit in year 5. In the multivariable Cox proportional hazards model for mortality at 5 years, each one-standard-deviation decrease in CMI was associated with 28% higher risk in mortality (HR 1.277, 95% CI 1.086-1.502, p = 0.003). Cardiovascular events occurred in 605 (34.9%) participants. Each standard deviation increase in WHR was significantly associated with 16% higher risk of cardiovascular events at 5 years (HR 1.160, CI 1.037-1.298, p = 0.009). Three hundred six (24.8%) participants evidenced CKD progression. In a multivariable binary logistic regression analysis, lower CMI was associated with a higher risk of progression of CKD at 5 years (OR 1.230, CI 1.028-1.471, p = 0.024). CONCLUSION:Lower CMI was independently associated with higher mortality and CKD progression, whereas higher WHR was independently associated with increased risk of cardiovascular events. These simple and inexpensive surrogate biomarkers of sarcopenia and visceral adiposity can be easily incorporated into daily practice to enhance risk stratification in people with CKD and inform therapeutic interventions to improve their clinical outcomes.
BACKGROUND:Measured urine albumin-to-creatinine ratio (ACR) is known to be variable between measurements from the same individual with chronic kidney disease (CKD) or diabetes, but the factors predisposing to increased variability remain unclear. Our objective was to quantify and identify predictors of short-term, within-person variability in albuminuria in a generalizable population. METHODS:This is a cross-sectional analysis of 4,829 adults in the 2009-2010 United States National Health and Nutrition Examination Survey who provided two urine samples within 10 days. We calculated the absolute percentage change, within-person coefficient of variation, and 95% reference change values for the overall population and within clinically meaningful subgroups. We then performed linear regression modeling to assess for a priori selected predictors of variability. RESULTS:The mean age was 47.8 (SD 16.5) years, the mean eGFR was 95.8 (SD 20.4) ml/min per 1.73m2, 11.3% had diabetes, and 51.5% of the participants were women. Factors associated with greater variability in temporally proximate repeat urine ACR samples included age, sex, and severity of initial urine ACR. Overall, albuminuria varied by approximately 28%, but there was heterogeneity within clinical subgroups. Reclassification into alternative albuminuria category following the second collection was low. CONCLUSION:Patients' urine ACR can fluctuate roughly ±30% on average and confirmatory testing is wise in those with borderline values. Reviewing longitudinal trends in urine ACR or averaging several collections is likely more clinically meaningful than any single value.
